S ugammadex messina

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sugammadex,modified cyclodextrins

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S ugammadex messina

  1. 1. Le gammaciclodestrine: Sugammadex C.Melloni Libero professionista Messina,4 ottobre 2012),I-SIVA
  2. 2. Referenze biblio  Ci sono 220 articoli in PubMed sul Sugammadex……………..(8 settembre 2012) Display Settings:Summary,20 per page, Sorted by Recently Added Send to:<< First< Prev Page of 11 Next >Last >> Results: 1 to 20 of 220 Filters activated: Abstract available Clear all Messina ,4 ottobre 2012),I-SIVA
  3. 3. Organizzazione della lettura SAR  La paralisi residua?  Antagonismo del blocco;TIVa;inalatoria  Antagonismo confronto AchE  Rescue per CV CI  Antagonismo anafilassi  Considerazioni sul monitoraggio;a good drug……….  Messina,4 ottobre 2012,I-SIVA
  4. 4. Utilizzi delle ciclodestrine(CD) Rajeswari Challa, Alka Ahuja, Javed Ali, R.K. Khar.Cyclodextrins in Drug Delivery.AAPS PharmSciTech 2005; 6 (2)  Formano complessi di inclusione con importanti modificazioni nelle proprietà dei farmaci,quali aumento di solublità,aumento della stabilità chimica e fisica » Nuovi modi di somministrare farmaci:liposomi, microsfere, microcapsule, nanoparticelle » Solubilità, » dissoluzioine, » biodisponibilità, » sicurezza , » stabilità, » eccipienti .  ,ecc,ecc………….. Messina,4 ottobre 2012,I-SIVA
  5. 5. RELAZIONE STRUTTURAATTIVITÀ Messina,4 ottobre 2012,I-SIVA
  6. 6. New reversal agents:i nuovi antagonisti Concetto della chelazione chimica  Le ciclodestrine sono un gruppo di oligosaccaridi capaci di incapsulare molecole lipofiliche,tra cui anche gli steroidi. 
  7. 7. Referenze in Pubmed.(sept 2003)  Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, MacLean EJ, Muir AW, Palin R, Rees DC, Zhang MQ. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl. 2002 Jan 18;41(2):266-70.  Sparr HJ. Cyclodextrin. A new concept for antagonizing muscle relaxants] Anaesthesist. 2002 Nov;51(11):929-30.
  8. 8. Prof.Bom Messina,4 ottobre 2012,I-SIVA
  9. 9. Referenze in Pubmed.(sept 2003):nascita chimico-fisica Epemolu O, Mayer I, Hope F, Scullion P, Desmond P. Liquid chromatography/mass spectrometric bioanalysis of a modified gammacyclodextrin (Org 25969) and Rocuronium bromide (Org 9426) in guinea pig plasma and urine: its application to determine the plasma pharmacokinetics of Org 25969. Rapid Commun Mass Spectrom. 2002;16(20):1946-52.  Adam JM, Bennett DJ, Bom A, Clark JK, Feilden H, Hutchinson EJ, Palin R, Prosser A, Rees DC, Rosair GM, Stevenson D, Tarver GJ, Zhang MQ. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. J Med Chem. 2002 Apr 25;45(9):1806-16.  Tarver GJ, Grove SJ, Buchanan K, Bom A, Cooke A, Rutherford SJ, Zhang MQ. 2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker rocuronium bromide. Bioorg Med Chem. 2002 Jun;10(6):1819-27. 
  10. 10. • The structure of gamma cyclodextrin is called a TORROID • It contains a hydrophilic exterior and a lipophilic interior • The hydrophilic exterior makes it water soluble , while the interior acts as a host for guest molecules to get encapsulate
  11. 11. • UNMODIFIED GAMMA CYCLODEXTRIN HAS A LARGE LIPOPHILIC CAVITY • BUT IT IS STILL NOT ROOMY TO ACCOMMODATE ROCURONIUM
  12. 12. • Eight sugar side chains are added to make the gamma cyclodextrin bigger to accommodate the rocuronium molecule • Ethyl carboxyl groups are added to these side chains to provide negative charges to hold the rocuronium electrostatically • SU = sugar GAMMADEX = gammacyclodextrin
  13. 13. STUCTURE OF ROCURONIUM
  14. 14. Messina,4 ottobre 2012,I-SIVA
  15. 15. Messina,4 ottobre 2012,I-SIVA
  16. 16. Messina,4 ottobre 2012,I-SIVA
  17. 17. Rocuronium incapsulato nella gammaciclodestrinaCrystal spectroscopy image of sugammadex encapsulating a rocuronium molecule. Reprinted with permission from Zhang M-Q. 2003. Drug-specifi c cyclodextrins: The future of rapid neuromuscular block reversal? Drugs Future, 28: 347–54. Copyright© 2003 Prous Scientifi c and Organon USA, a part of Schering-Plough Corporation
  18. 18. BRITISH JOURNAL OF ANAESTHESIA Volume 97, Number 2, August 2006 British Journal of Anaesthesia 97 (2): 123– 6 (2006) Editorial The doughnut and the hole: a new pharmacological concept for anaesthetists Messina,4 ottobre 2012,I-SIVA
  19. 19. Messina,4 ottobre 2012,I-SIVA
  20. 20. Messina,4 ottobre 2012,I-SIVA
  21. 21. Messina,4 ottobre 2012,I-SIVA
  22. 22. X-ray crystal structures of Org 25969 (green) and rocuronium (blue) with filled van der Waals surface Messina,4 ottobre 2012,I-SIVA
  23. 23. Messina,4 ottobre 2012,I-SIVA
  24. 24. Messina,4 ottobre 2012,I-SIVA
  25. 25. Complesso solubile sugammadex rocuronium Messina,4 ottobre 2012,I-SIVA
  26. 26. Encapsulation process: Sugammadex carboxyl groups interact with steroidal rings A, B, C, and D, drawing the aminosteroidal NMBA molecule into the cavity where additional non-covalent attractions hold the molecule securely in place. Messina,4 ottobre 2012,I-SIVA
  27. 27. Sugammadex encapsulates aminosteroidal NMBA molecules in the plasma causing a concentration gradient that favors the extraction of additional rocuronium molecules from the nicotinic junction into the plasma Messina,4 ottobre 2012,I-SIVA
  28. 28. young elderly Old Messina,4 ottobre 2012,I-SIVA Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuroniuminduced Neuromuscular Blockade in Elderly Patients.David L. McDonagh,, Patrick E. Benedict, Anthony L. Kovac, ,David R. Drover,, Neil W. Brister, Jovino B. Morte, Terri G. Monk.Anesthesiol ogy 2011:114;218
  29. 29. Messina,4 ottobre 2012,I-SIVA
  30. 30. Benefici attesi con Sugammadex Aumentata sicurezza per I pazienti  Aumentata sicurezza in anestesia e chirurgia  Ridotta incidenza(eliminazione) del blocco nm residuo  Aumentata effficienza  » Benefici economici per accelerazione della ripresa,turnover + rapido? Messina,4 ottobre 2012,I-SIVA
  31. 31. Messina,4 ottobre 2012,I-SIVA
  32. 32. Effficacia clinica Antagonismo di blocco nm moderato  Antagonismo di blocco nm profondo  Antagonismo immediato del blocco nm  Antagonismo con farmaci comparatori  Confronto con gli effetti avversi degli altri antidoti dei NMBA  Messina,4 ottobre 2012,I-SIVA
  33. 33. Summary of time (minutes) from start of administration of sugammadex or placebo to recovery of TOF ratio to 0.7, 0.8 and 0.9 in placebocontrolled trials of sugammadex for reversal of moderate nmmb. Min 100 90 80 70 60 50 tof0,7 40 30 tof 0,8 20 10 Puhringer 0 Sorgenfrei Messina,4 ottobre 2012,I-SIVA Soy tof 0,9
  34. 34. Spontaneous vs sugammadex reversal following rocuronium 0.6 mg/kg Messina,4 ottobre 2012,I-SIVA
  35. 35. Summary of time (minutes) from start of administration of sugammadex or neostigmine to recovery of TOF ratio to 0.7, 0.8 or 0.9 in active-control studies of sugammadex for reversal of moderate nmb min Messina,4 ottobre 2012,I-SIVA
  36. 36. SUGAMMADEX IN BLOCCHI PROFONDI Messina,4 ottobre 2012,I-SIVA
  37. 37. Results from studies of sugammadex for reversal of profound NMB 140 Reversal at 15 min 120 100 80 tof 0,7 tof 0,8 60 40 tof 0,9 Sparr Puhringer 20 0 rocu0,6+sugamma rocu 0,6 spont rocu1+sugamma Messina,4 ottobre 2012,I-SIVA rocu1 spont rocu1,2+sugamma rocu 1,2 spont
  38. 38. Results from studies of sugammadex for reversal of profound NMB at PTC 1-2 Tof 0.9 Messina,4 ottobre 2012,I-SIVA
  39. 39. Time to recovery of TOF ratio to 0.9 (min) in the studies comparing different doses of sugammadex for reversal of vecuronium or pancuronium-induced neuromuscular blockade 70 min 60 50 panc Decoopman 2007 40 Duvaldestin 2007 vecu 30 Puhringer 2007 20 10 0 Sugammadex mg/kg Messina,4 ottobre 2012,I-SIVA 2 0.5 1 4 6 8
  40. 40. VEDIAMO UN LAVORO IN DETTAGLIO………… Messina,4 ottobre 2012,I-SIVA
  41. 41. Tempo di ricomparsa del tofr dopo antagonismo a vari dosaggi di sugammadex(mg/kg) di rocuronium 0.6 mg/kg e vecuronium 0.10 mg/kg Koen Suy, Karl Morias,,Guy Cammu, , Pol Hans, Wilbert G. F. van Duijnhoven, Marten Heeringa, Ignace Demeyer. Effective Reversal of Moderate Rocuronium- or Vecuronium-induced Neuromuscular Block with Sugammadex, a Selective Relaxant Binding Agent.Anesthesiology 2007;106:283-8 min
  42. 42. Estimated dose–response relation of sugammadex dose and time to recovery of the T4/T1 ratio to 0.9 in the rocuronium 0.60 mg/kg group (per-protocol population; adapted weighted regression). T4/T1 ratio is the amplitude of the fourth response [T4] over the first response [T1] to train-of-four stimulation. CI confidence interval.
  43. 43. Estimated dose–response relation of sugammadex dose and time to recovery of the T4/T1 ratio to 0.9 in the vecuronium 0.10 mg/kg group (per-protocol population). T4/T1 ratio is the amplitude of the fourth response [T4] over the first response [T1] to train-of-four stimulation. CI confidence interval. One data point of 88:21 min is not shown
  44. 44. Rocuronium deep block > 2 h;reversal with different dosages of Sugammadex (Shields ,BJA 2006,96,36.) tofr 0.9 min 6 5 4 3 tofr 0.9 2 1 0 sugammadex 0,5 mg/kg 1,0 mg/kg 2,0 mg/kg Messina,4 ottobre 2012,I-SIVA 4,0 mg/kg 6 mg/kg
  45. 45. SUGAMMADEX SUBITO DOPO ROCURONIUM Messina,4 ottobre 2012,I-SIVA
  46. 46. Summary of time to recovery in placebo-controlled trials of sugammadex for rapid reversal of rocuronium-induced NMB 140 Puhringer 120 100 3 min dopo rocu 80 De Boer 5 min dopo rocu 60 tof 0,7 3 min dopo rocu 40 20 0 rocu1 +sugamma 16 rocu 1 spont rocu 1.2+sugamma 16 Messina,4 ottobre 2012,I-SIVA rocu 1.2 spont rocu1,2+sugamma rocu 1,2 spont #REF! tof 0,9
  47. 47. ROCU + SUGAMMADEX VS SUCCI Messina,4 ottobre 2012,I-SIVA
  48. 48. Summary of time to recovery after rocuronium + sugammadex 16 mg/kg after 3 min and Succinylcholine 1 mg/kg spont recovery min 12 10 8 rocu + sugammadex 6 Succi 1 mg/kg 4 2 0 T 1 10% T 1 90% Messina,4 ottobre 2012,I-SIVA tof 0,9
  49. 49. Rapid sequence induction and intubation with rocuroniumsugammadex compared with succinylcholineBr J Anaesth. 2012 ;108:682- 9.Rapid sequence induction and intubation with rocuronium-sugammadex compared with succinylcholine: a randomized trial.Sørensen MK, Bretlau C, Gätke MR, Sørensen AM, Rasmussen LS randomized ,patient- and observer-blinded  GA ,elective surgical patients, RSI alfentanil (10 µg /kg, propofol (2 mg/kg  Scc 1 mg/kg vs rocuronium 1 mg/kg  After tracheal intubation, Sugammadex (16 mg/kg vs spont.until a respiratory rate > 8/min and TV >3 ml/kgfor 30 s.  Messina,4 ottobre 2012,I-SIVA
  50. 50. Br J Anaesth. 2012 ;108:682-9.Rapid sequence induction and intubation with rocuronium-sugammadex compared with succinylcholine: a randomized trial.Sørensen MK, Bretlau C, Gätke MR, Sørensen AM, Rasmussen LS sec Median times 600 500 400 rocu+sugamm Succi 300 200 100 0 Spont resp Messina,4 ottobre 2012,I-SIVA T1 90%
  51. 51. Rocu 0,6 mg followed at 3 min by placebo or sugammadex 8 mg/kg The blue line represents the height of the twitch, and the dashed red line is the value of the trainof-four ratio. No recurarization was observed in the 90 min during which the neuromuscular block was monitored. Messina,4 ottobre 2012,I-SIVA
  52. 52. Rocuronium reversal with sugammadex during propofol or sevoflurane anesthesia Messina,4 ottobre 2012,I-SIVA
  53. 53. Sugammadex reversal following vecu or rocu Messina,4 ottobre 2012,I-SIVA
  54. 54. Sugammadex per il rovesciamento immediato di un blocco nm con dose elevata di rocuronium tof 0.9 min 3.5 3 2.5 2 1.5 1 0.5 0 8 Messina,4 ottobre 2012,I-SIVA 12 16 mg/kg
  55. 55. Sugammadex 2 mg/kg vs 8 mg/kg reversal 3 min after rocuronium Messina,4 ottobre 2012,I-SIVA
  56. 56. Antagonismo dei miorilassanti
  57. 57. Presenza dei vapori….
  58. 58. Recovery parameters following neostigmine administration min (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) 20 18 16 14 12 10 8 6 4 2 0 6 groups ,20 each Rocuronium, Force, neo at tof 25%! * ** * prop prop sevo sevo iso iso cont stop cont stop cont stop onset Tof 0.80 RI pts at 0.8 tof at 15 min
  59. 59. 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)
  60. 60. 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- )
  61. 61. • Insomma,continuare la soministraz del vapore ritarda la ripresa nm anche dopo rovesciamento……
  62. 62. Neo vs edrofonio e profondità del blocco nm.
  63. 63. 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%
  64. 64. 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. ??? ? Inspired enflurane concentration maintained at 0.5-1%
  65. 65. Effect on Tof of 2 doses of neostigmine and edrophonium following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose-Res Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 37-43. 80 70 Inspired enflurane concentration maintained at 0.5-1% Tof si ferma a 0.7!!! 60 50 atrac at 5' atrac at 10' vecu at 5' vecu at 10' 40 30 20 10 0 neo 0.02 mg/kg neo 0.04 mg/kg edroph 0.5 mg/kg edroph 1 mg/kg
  66. 66. Conclusione 1 • La dose giusta di neostigmina è………… • Meditate gente meditate………………
  67. 67. 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.
  68. 68. Conclusione 2 • E’ meglio somministrare gli antidoti quando la ripresa nm è iniziata • È meglio cessare la somministrazione degli alogenati ( e monitorizzare la % et)…….
  69. 69. Effetti collaterali degli anti AchE
  70. 70. Effetti fisiologici della presenza di Ach • • • • Bradicardia Salivazione Iperperistalsi Secrezioni bronchiali
  71. 71. Pericoli degli AntiAchE: arresto cardiaco • Bjerke, Richard J., MD; Mangione, Michael P.Asystole after intravenous neostigmine in a heart transplant recipinet.Can.Anaesth.J. 2001;48:30507. • • • 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.
  72. 72. 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.
  73. 73. 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;45:1190-95 Purpose: 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. Neostigmineor 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.
  74. 74. Schema delle afferenze parasimpatiche a livello tracheale
  75. 75. 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
  76. 76. NEOSTIGMINE AND PONV
  77. 77. 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 (numberneeded-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.
  78. 78. Risk of omitting neostigmine…. • Residual paralysis!!!
  79. 79. 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 1-2 Posponi antagonismo finchè almeno 1 o 2 contrazioni visibili!! ++++ neostigmina 0.07 mg/kg 3-4 +++ neostigmina 0.04 mg/kg 4 ++ edrofonio 0.5 mg/kg 4 +/- edrofonio 0.25
  80. 80. PORC % nella metanalisi di Naguib Br J Anaesth. 2007 Mar;98(3):302-16.Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis.Naguib M, Kopman AF, Ensor JE. panc Dtc Galla panc panc Atrac 0 galla vari Atrac 0 panc Panc vecu Panc vecu panc tof70 Tof 90 Messina,4 ottobre 2012,I-SIVA
  81. 81. Messina,4 ottobre 2012,I-SIVA
  82. 82. PORC % nella metanalisi di Naguib ;parte II 100 90 80 70 60 50 40 tof <0.70 tof < 0.90 30 20 10 0 Messina,4 ottobre 2012,I-SIVA
  83. 83. incidence of PORC was more frequent after the use of traditional long-acting neuromuscular blocking drugs(da Naguib) Messina,4 ottobre 2012,I-SIVA
  84. 84. Ma la PORC perchè è importante?
  85. 85. Viby Mogensen et al,AAS 1997 • • • • 693 paz.randomizzati,cieco chir elettiva monitoraggio periop con Myotest e Tof confronto fra 1-5-2 ED95 di atrac,vecu,panc. • Antagonismo se necessario; • estubaz a tof eguale, tattile e resp adeguata.
  86. 86. Paralisi residua e % di tof<0.40 in RR,subito dopo trasferimento 45 40 35 30 panc atrac vecu 25 20 15 10 5 0 Tof <0.70 tof<0.40
  87. 87. % tof<0.80 Andamento temporale del tof <0.80 nella RR 50 45 40 35 30 25 20 15 10 5 0 panc atrac vecu 0 5 10 15 20 min 30 40 50
  88. 88. Postoperative pulmonary complications 20 15 10 % atrac vecu panc 5 0 popc popc con popc senza blocco blocco residuo residuo panc vecu atrac
  89. 89. Popc secondo il tipo di chirurgia 16 14 12 10 addom ortop ginecol % 8 6 4 2 0 popc
  90. 90. Fattori di rischio per POPC nello studio AAS1997 Tipo di chirurgia;freq * 2-10(addominale) età:ogni 10 anni * 1.68 durata di anestesia(> o < 200 min)*3.3 panc e tof<0.70:*5
  91. 91. Eur J Anaesthesiol. 201128(12):842-8. The influence of residual neuromuscular block on the incidence of critical respiratory events. A randomised, prospective, placebo-controlled trial. Sauer M, Stahn A, Soltesz S, Noeldge-Schomburg G, Mencke T. • Department of Anaesthesiology and Intensive Care Medicine, University of Rostock, Rostock, Germany. • incidence of critical respiratory events, such as hypoxaemia, in patients with minimal residual neuromuscular blockade and compared these data with those from patients with full recovery of blockade. • Randomised, prospective, placebo-controlled trial. • 132 adult patients, 18-80ASA I-III ,orthopaedic surgery ,GA with rocuronium • randomised to one of two groups: neostigmine group (neostigmine 20 μg kg-1) or placebo group (saline). • In the patients in the neostigmine group, the tracheal tube was removed at a train-offour (TOF) ratio of 1.0; in the patients in the placebo group, the trachea was extubated at a TOF ratio less than 1.0, but without fade in TOF and double-burst stimulation (DBS). • Neuromuscular monitoring was assessed simultaneously with qualitative TOF/DBS monitoring, and with quantitative calibrated acceleromyography. • Critical respiratory events, such as hypoxaemia, were assessed in the post-anaesthesia care unit.
  92. 92. The influence of residual neuromuscular block on the incidence of critical respiratory events. A randomised, prospective, placebo-controlled trial • 45 pts (39.5%) became hypoxaemic (SaO2 < 93%); • there was a significant difference between the groups (29 patients in the placebo group versus 16 in the neostigmine group; P = 0.021). • In the neostigmine group, all patients were extubated at a TOF ratio of 1.0. In the placebo group, the median TOF ratio was 0.7 (range: 0.46-0.9; P < 0.001). The median time for spontaneous recovery in the placebo group was 16 min (range 3-49 min). Neostigmine 20 μg kg was effective in antagonising rocuronium-induced blockade without fade in TOF and DBS. • In this randomised, prospective, placebo-controlled trial, minimal residual block was associated with hypoxaemia in the post-anaesthesia care unit. Neostigmine 20 μg kg was effective in antagonising rocuronium-induced (minimal) blockade
  93. 93. MA CHE CI IMPORTA DEL TOFR 0.90?
  94. 94. 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
  95. 95. 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  Messina,4 ottobre 2012,I-SIVA
  96. 96. 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??  Messina,4 ottobre 2012,I-SIVA
  97. 97. 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 trainof-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 Messina,4 ottobre 2012,I-SIVA
  98. 98. 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  Messina,4 ottobre 2012,I-SIVA
  99. 99. 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 applico ad una ampia gamma di situazioni cliniche. Esistono pesanti pressioni economiche per la diminuzione della spesa sanitaria. Messina,4 ottobre 2012,I-SIVA
  100. 100. 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. Messina,4 ottobre 2012,I-SIVA
  101. 101. 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 )? Messina,4 ottobre 2012,I-SIVA
  102. 102. Maybauer D,Geldner G,Blobner M et al.Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium.Anaesthesia 2007;62:12-17. % or min Incidence of residual paralysis after cisatracurium and rocuronium 100 80 60 40 20 0 cisatracurium rocuronium incid of residual paralysis Time between skin closure and extubation Messina,4 ottobre 2012,I-SIVA T4 T1 0.9 Variab of duration
  103. 103. Ipossia Chemrorecet perif ipercapnia Chemrecett.centr SNC iperventilazione
  104. 104. nmb Sito nicotinico ipossia Corpi carotidei Sito muscari nico atropina
  105. 105. Conclusioni • Esiste evidenza sperimentale e clinica che i nmb nondepolarizzanti interferiscano con il controllo della ventilazione in condizioni di ipossia,verosimilmente attraverso una depressione reversibile della attività chemorecettoriale dei corpi carotidei implicazioneclinica
  106. 106. SUGAMMADEX IN SPECIAL POPULATIONS Messina,4 ottobre 2012,I-SIVA
  107. 107. Sugammadex is not influenced by renal insufficiency Staals LM, Snoeck MM, Driessen JJ, Flockton EA, Heeringa M, Hunter JM. Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function. Br J Anaesth 2008;101:492-7. Messina,4 ottobre 2012,I-SIVA
  108. 108. Bom AH,Hope H. Rapid reversal of rocuronium induced neuromuscular block by ORG 25969 in the guinea pig is not modified by occlusion of the blood supply to one kidney.Eur J,Anesth.20003;20:suppl A 486 12 2 kidneys 1 kidney 10 8 min 6 4 2 0 spont org 25969 69 org 25969 230 org 25969 460 mmol/kg mmol/kg mmol/kg
  109. 109. Minerva Anestesiol. 2012 Jan;78(1):112-3. Prolonged neuromuscular block associated to non-alcoholic steatohepatitis in morbidly obese patient: neostigmine versus sugammadex.Carron M, Parotto E, Ori C.  Paz MO dopo sleeve gastrectomy; a 150 min dal rocu la neostigmina non supera Tof 0.20;sugammadex 2 mg/kg normalizza in 2 min.! Messina,4 ottobre 2012,I-SIVA
  110. 110. Obese patients  Somministrare la dose sul peso reale ,non IBW! » Anesthesiology. 2012 Jul;117(1):93-8.Sugammadex ideal body weight dose adjusted by level of neuromuscular blockade in laparoscopic bariatric surgery.Llauradó S, Sabaté A, Ferreres E, Camprubí I, Cabrera A. Messina,4 ottobre 2012,I-SIVA
  111. 111. Per saperne di +:review  Anaesthesia. 2009 Mar;64 Suppl 1:55-65.Neuromuscular blocking drugs and their antagonists in patients with organ disease.Craig RG, Hunter JM. Messina,4 ottobre 2012,I-SIVA
  112. 112. Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuroniuminduced NeuromuscularBlockade in Elderly Patients.David L. McDonagh,, Patrick E. Benedict, Anthony L. Kovac, ,David R. Drover,, Neil W. Brister, Jovino B. Morte, Terri G. Monk.Anesthesiology 2011:114;218  adult (aged 18–64 yr) versus elderly adult (aged 65 yr or older) patients. phase 3a, multicenter, parallel-group, comparative,open-label study 162 patients ASA 1–3, rocuronium, 0.6 mg/kg + maintenance doses of 0.15 mg/kg as required. At the end of surgery, patients received sugammadex, 2.0 mg/kg, at reappearance of the second twitch of TOF primary efficacy variable was time from sugammadex administration to recovery of the TOF ratio to 0.9 or greater.  Pharmacokinetics ottobre 2012,I-SIVA were also evaluated. and safety Messina,4      
  113. 113. Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-induced NeuromuscularBlockade in Elderly Patients.David L. McDonagh,, Patrick E. Benedict, Anthony L. Kovac, ,David R. Drover,, Neil W. Brister, Jovino B. Morte, Terri G. Monk.Anesthesiology 2011:114;218     Results: Overall, 150 patients were treated and had at least one postbaseline efficacy assessment; 48 were aged 18–64 yr (adult), 62 were aged 65–74 yr (elderly), and 40 were aged 75 yr or older (old-elderly). The geometric mean time (95% confidence interval) from sugammadex administration to recovery of the TOF ratio to 0.9 increased with age, from 2.3 (2.0 –2.6) min (adults) to 2.9 (2.7–3.2) min (elderly/oldelderly groups combined). Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in adults compared with patients aged 65 yr or older (P 0.022). Sugammadex was well tolerated by all patients. Messina,4 ottobre 2012,I-SIVA
  114. 114. Individual patient recovery times to a TOF ratio of 0.9 Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-induced NeuromuscularBlockade in Elderly Patients.David L. McDonagh,, Patrick E. Benedict, Anthony L. Kovac, ,David R. Drover,, Neil W. Brister, Jovino B. Morte, Terri G. Monk.Anesthesiology 2011:114;218 geometric mean time sugammadex administration to TOFr 0.9 increased with age, from 2.3 (2.0 –2.6) min (adults) to 2.9 (2.7–3.2) min (elderly/oldelderly groups combined). 0.7 min faster in adults compared with patients aged 65 yr or older Messina,4 ottobre 2012,I-SIVA
  115. 115. Messina,4 ottobre 2012,I-SIVA
  116. 116. SAFETY Messina,4 ottobre 2012,I-SIVA
  117. 117. J Smooth Muscle Res. 2012;48(2-3):59-64.Effect of sugammadex on bronchial smooth muscle function in rats. Yoshioka N, Hanazaki M, Fujita Y, Nakatsuka H, Katayama H, Chiba Y   . Sugammadex can encapsulate the steroid-based neuromuscular blocker molecule and results in rapid reversal of neuromuscular blockade induced by rocuronium and vecuronium. However, several cases of bronchospasm after the administration of sugammadex have been reported. The current study was carried out to determine whether sugammadex directly affects smooth muscle function of the airways. The ring strips of left main bronchi were isolated from male Wistar rats and isometric forces were measured. In the isolated bronchial smooth muscle tissues, sugammadex (10<sup>-8</sup> - 10 <sup>-3</sup> M) had no effect on baseline tension or the acetylcholine (ACh; 30 µM)-induced sustained contraction. Moreover, sugammadex did not affect bronchial smooth muscle responsiveness to ACh. These findings indicate that sugammadex itself does not affect contractile function in bronchial smooth muscle of the rat Messina,4 ottobre 2012,I-SIVA
  118. 118. Effect of sugammadex or saline on Rhesus monkey Messina,4 ottobre 2012,I-SIVA
  119. 119. Gamma ciclodestrina non ha attività biologica!  Pochissimi effetti collaterali durante la sperimentazione;  » KO anestetiche e 1 caso di possibile reazione allergica (= ai comparatori) Messina,4 ottobre 2012,I-SIVA
  120. 120. Urinary N-acetyl-glucosaminidase (NAG) as a measure of proximal tubule damage  Valori anormali : » Sorgenfrei et al.:5/22 pts » Sparr et al.: 2/88 pts + microalbuminuria in » 4 + 3 con anormali concentrazioni di b2microglobulin concentration » Flockton et al. : 7/34 »Significato???? Messina,4 ottobre 2012,I-SIVA
  121. 121. Affinità per altre molecole Per cortisone,idrocortisone,aldosterone <120 volte del rocu  Per atropina.verapamil,ketamina da 400 a 700 volte < rocuro  Contraccettivi orali?  » Dobbiamo informare le pazienti????????? Messina,4 ottobre 2012,I-SIVA
  122. 122. Interazioni significative Tamoxifene 17%  Noretindrone 14%  Betametasone 7%  Estradiolo 7%  Flucloxacina ?  Acido fusidico?  Toremifene?  Messina,4 ottobre 2012,I-SIVA Clin Drug Investig. 2011;31(2):101-11. Assessment of the potential for displacement interactions with sugammadex: a pharmacokinetic-pharmacodynamic modelling approach..Zwiers A, van den Heuvel M, Smeets J, Rutherford
  123. 123.  Eikermann M, Zaremba S, Malhotra A, et al. Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing. Br J.Anaesth 2008; 101:344–349. Messina,4 ottobre 2012,I-SIVA
  124. 124. Int J Clin Pharmacol Ther. 2012 ;50:595-604.Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study.de Kam PJ, van Kuijk J, Smeets J, Thomsen T, Peeters P.   Clinical Pharmacology, Merck Sharp & Dohme Corp., Whitehouse Station, NJ 07065-0900, USA. pieterjan.de.kam@merck.com Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI).  METHODS:  Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), Messina,4 ottobre 2012,I-SIVA in this randomized, double-blind, cross-over study, healthy volunteers
  125. 125. Uso clinico del sugammadex  Antagonismo alla fine dell’intervento: » Tof 1-2; 2mg/kg » Ptc 1-2:4 mg/kg Se dopo sugammadex è urgente ricurarizzare il poaziente(sanguinamento);atrac,cisatrac!  Intubazione difficile imprevista dopo bolo di rocu; sugammadex 16 mg/kg  È costoso:Uso selettivo?Malattie neuro muscolari,insuff epatica,insuff renale,chir amb,C/S …..  Messina,4 ottobre 2012,I-SIVA
  126. 126. E se bisogna ricurarizzare urgentemente il paziente dopo rovesciamento con Sugammadex? Utilizza un miorilassante non steroideo;cisatracurium,atracurium… Oppure……… Messina,4 ottobre 2012,I-SIVA
  127. 127. Altri vantaggi del sugammadex Riduzione del tempo di ripresa:aumento dell’efficienza di sala op;diminuzione del soggiorno in TIPO………….  Riduzione della severità della reazione allergica da rocu e vecu:  » -Can sugammadex encapsulation eliminate the antigenic activity of aminosteroidal neuromuscular blocking agent?Kawano T, Yokoyama M.. » J Anesth. 2011 Dec;25(6):953-4. Epub 2011 Sep 9. No abstract available. » -Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker rocuronium and perioperative anaphylaxis: implications for drug allergy.Baldo BA, McDonnell NJ, Pham NH.. » Clin Exp Allergy. 2011 Dec;41(12):1663-78. doi: 10.1111/j.1365-2222.2011.03805.x. Epub 2011 Jul 7. Review. Messina,4 ottobre 2012,I-SIVA
  128. 128. Sugammadex and rocuronium allergy/anaphylaxis  The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model.Clarke RC, Sadleir PH, Platt PR.Anaesthesia. 2012 Mar;67(3):266-73.  [Fast recovery of haemodynamic and ventilatory functions after sugammadex bolus following rocuronium-induced anaphylactic shock refractory to conventional treatment].Raft J, Leclercq M, Longrois D, Meistelman C.Ann Fr Anesth Reanim. 2012 Feb;31(2):158-61. 3.  Successful management of rocuroniuminduced anaphylactic reactions with Messina,4 ottobre 2012,I-SIVA
  129. 129. Health Technology Assessment 2010; Vol. 14: No. 39 Health Technology. Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment D Chambers, M Paulden, F Paton, M Heirs, S Duffy, D Craig, J Hunter, J Wilson, M Sculpher and N Woolacott ASSESSMENT OF COST-EFFECTIVENESS EVIDENCE Messina,4 ottobre 2012,I-SIVA
  130. 130. associated with sugammadex and value of each minute of recovery time saved at which sugammadex is (is not) cost-effective under the base-case assumptions for each scenario. Separate graphs are plotted for rocuronium- and vecuronium-induced blockade and for moderate and profound blockade.The horizontal dashed (dotted) line represents an estimate of the value of each minute saved were all the time savings to occur in the operating room (recovery room), while the dotted and dashed vertical line represents an estimate of the reduction in recovery time associated with sugammadex (see Routine reversal of neuromuscular block, Methods). Messina,4 ottobre 2012,I-SIVA
  131. 131. Bridion® Organon N.v  ev 10 fl 100 mg/ml 2 ml - € 819,95* - € 667,85**; » 2 mg/kg in paz di 70 kg:200 mg,1 fiala,82-67 euro » 4 mg/kg in paz di 70 kg ;280 mg ,1 fiala e mezzo,122102 euro  ev 10 fl 100 mg/ml 5 ml - € 2.049,85* - € 1669,62** » 16 mg/kg in paz di 70 kg 1120 mg,2 fiale da 500 e 1 da 100=410+82=500 euro… Messina,4 ottobre 2012,I-SIVA
  132. 132. Messina,4 ottobre 2012,I-SIVA
  133. 133. E’ POSSIBILE UN REBOUND DI MIORILASSANTE SE LA DOSE DI SUGAMMADEX È INSUFFICIENTE? Messina,4 ottobre 2012,I-SIVA
  134. 134. Douglas J. Eleveld,,Karel Kuizenga,,Johannes H. Proost, J. Mark K. H. Wierda, .Temporary Decrease in Twitch Response During Reversal of Rocuronium-Induced Muscle Relaxation with a Small Dose of Sugammadex. (Anesth Analg 2007;104:582–4) Messina,4 ottobre 2012,I-SIVA Temporary decrease TOF ratio and T1 during reversal of rocuroniuminduced muscle relaxation (0.9 mg/kg) with sugammadex (0.5 mg/kg administered 42 min after rocuronium). At the time of sugammadex administration the posttetaniccount (PTC) value was 1.
  135. 135. Rebound…       REBOUND might occur because redistribution of unbound muscle relaxant molecules from peripheral compartments back into central and effect compartments. After sugammadex administration,the concentration of unbound rocuronium molecules in the central compartment decreases rapidly,leading to a rapid decrease in muscle relaxation intensity. The decreased unbound rocuronium concentration in the central compartment leads to a redistribution of unbound rocuronium from peripheral compartments back into the central compartment. If insufficient sugammadex is present for additional complex formation, then this redistribution process will lead to a temporary increase in unbound rocuronium concentration in the central compartment and in the effect compartment. Thereafter, the unbound rocuronium concentration decreases because of clearance of the drug. that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. These observations support our hypothesis that rebound may occur because of redistribution of unbound muscle relaxant molecules from peripheral compartments back into central and effect compartments. Muscle relaxation rebound can therefore occur without dissociation of the sugammadex/ rocuronium complex. This implies that for a reliable reversal of neuromuscular blockade without muscle relaxation rebound, a sufficiently large dose of sugammadex is necessary. Presumably, the recommended Messina,4 ottobre 2012,I-SIVA doses of sugammadex under these conditions (PTC 1) will be larger than 0.5 mg/kg, and will thus prevent
  136. 136. Simulazione con dosi crescenti di sugammadex secondo un modello Pk Pd Observed train-of-four (TOF) data () and the results of simulations (solid lines) of various sugammadex dosing amounts. Muscle relaxation rebound only occurs for sugammadex doses in a limited range. The simulations indicate that for this patient, doses larger than about 1 mg/kg are sufficient to achieve rapid muscle relaxation reversal and avoid muscle Messina,4 ottobre 2012,I-SIVA . relaxation rebound
  137. 137. Che cosa ci manca ancora? Un sostituto non depolarizzante ad azione rapida più della succinilcolina( o per lo meno simile….)  Che il sugammadex sia impiegato in milioni di casi in modo che si possa vedere qualche effetto collaterale…  Messina,4 ottobre 2012,I-SIVA
  138. 138. PICO Question:  P- In patients requiring neuromuscular blockade reversal  I- is the selective relaxant binding agent (SRBA) sugammadex an improvement on  C- cholinesterase inhibitors  O- for more effective reversal, less side effects and greater safety profile? Messina,4 ottobre 2012,I-SIVA
  139. 139. FINEEEEEE Messina,4 ottobre 2012,I-SIVA
  140. 140. Messina,4 ottobre 2012,I-SIVA
  141. 141. Posterior predictive check of the pharmacokinetic–pharmacodynamic model for sugammadex-mediated reversal times [time to train-of-four ratio of 0.9 (TOF90)] of rocuronium-induced neuromuscular block, observed (OBS) and predicted (PRED) reversal times. Crosses represent individual values, bars represent range and horizontal lines represent the median.Relative difference between reversal times [(OBS–PRED)/OBS ¥ 100] is presented above the bars Messina,4 ottobre 2012,I-SIVA
  142. 142. Posterior predictive check of the pharmacokinetic–pharmacodynamic model for sugammadexmediated reversal times [time to train-of-four ratio of 0.9 (TOF90)] of rocuronium-induced neuromuscular block, observed (OBS) and predicted (PRED) reversal times. Crosses represent individual values, bars represent range and horizontal lines represent the median.Relative difference between reversal times [(OBS–PRED)/OBS ¥ 100] is presented above the bars Messina,4 ottobre 2012,I-SIVA
  143. 143. Posterior predictive check of the pharmacokinetic–pharmacodynamic model for sugammadex-mediated reversal times [time to train-of-four ratio of 0.9 (TOF90)] of rocuronium-induced neuromuscular block, observed (OBS) and predicted (PRED) reversal times. Crosses represent individual values, bars represent range and horizontal lines represent the median.Relative difference between reversal times [(OBS–PRED)/OBS ¥ 100] is presented above the bars Messina,4 ottobre 2012,I-SIVA
  144. 144. Posterior predictive check of the pharmacokinetic–pharmacodynamic model for sugammadexmediated reversal times [time to train-of-four ratio of 0.9 (TOF90)] of rocuronium-induced neuromuscular block, observed (OBS) and predicted (PRED) reversal times. Crosses represent individual values, bars represent range and horizontal lines represent the median.Relative difference between reversal times [(OBS–PRED)/OBS ¥ 100] is presented above the bars Messina,4 ottobre 2012,I-SIVA
  145. 145. Residual curarization Is the main problem? Messina,4 ottobre 2012,I-SIVA
  146. 146. Summary of studies without reversal Messina,4 ottobre 2012,I-SIVA
  147. 147. Summary of studies with reversal Messina,4 ottobre 2012,I-SIVA
  148. 148. burst stimulation decreases, but not eliminates, the problem of postoperative residual paralysis. Acta Anaesthesiol Scand 1998; 42:1168-74  BACKGROUND: Routine perioperative monitoring with acceleromyography 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 Messina,4 ottobre 2012,I-SIVA detectable in the TOF response, the stimulation pattern was
  149. 149. train-of-four monitoring and residual curarization. Can J Anaesth 1995; 42:71115.<ldn>!  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 Messina,4 ottobre 2012,I-SIVA in similar doses (Group A: 53 micrograms.kg-1 (5.9); Group B:
  150. 150. influence the frequency of postoperative residual neuromuscular blockade? Anesthesiology 1990; 73:835-9  The authors conducted a randomized controlled clinical trial to evaluate the usefulness of perioperative manual evaluation of the response to train-of-four (TOF) nerve stimulation. A total of 80 patients were divided into four groups of 20 each. For two groups (one given vecuronium and one pancuronium), the anesthetists assessed the degree of neuromuscular blockade during operation and during recovery from neuromuscular blockade by manual evaluation of the response to TOF nerve stimulation. In the other two groups, one of which received vecuronium and the other pancuronium, the anesthetists evaluated the degree of neuromuscular blockade solely by clinical criteria. The use of a nerve stimulator was found to have no effect on the dose of relaxant given during anesthesia, on the need for supplementary doses of anticholinesterase in the recovery room, on the time from end Messina,4 ottobreto end of anesthesia, or on the incidence of of surgery 2012,I-SIVA postoperative residual neuromuscular blockade evaluated
  151. 151. Recovery from neuromuscular blockade: residual curarisation following atracurium or vecuronium by bolus dosing or infusions. Acta Anaesthesiol Scand 1995; 39:288-93.  AB - We conducted a survey of the incidence of Postoperative Residual Curarisation (PORC) in two groups of patients following the use of atracurium or vecuronium. In the first group (B) the neuromuscular blocking drugs were administered by bolus dosing, and in the second group (I) by continuous fusion. On arrival in the recovery room, neuromuscular function was assessed both by compound evoked electromyogram (EMG) in a train of four pattern and also clinically, by the ability to sustain a headlift for > 5 seconds, and to cough. Results were obtained from 150 patients (100 in group B and 50 in group I). The incidence of PORC, as defined by a train of four ratio of < 0.7, on arrival in the recovery room was 12% in group B, and 24% in group I. Clinical criteria of adequate neuromuscular reversal revealed different results, with the majority of patients being unable toMessina,4 ottobre 2012,I-SIVA perform either clinical test on arrival in recovery. Those patients in whom a peripheral nerve stimulator was used intra-
  152. 152. Baillard C, Gehan G, Reboul-Marty J, Larmignat P, Samama CM, Cupa M. Residual curarization in the recovery room after vecuronium. Br J Anaesth 394-5; 2000:84.  2: Viby-Mogensen J, Jørgensen BC, Ørding M. Residual curarization in the recovery room. Anesthesiology 1979; 50:539-41.  Messina,4 ottobre 2012,I-SIVA
  153. 153. Reboul-Marty, J.2; Larmignat, P.1; Samama, C. M.1; Cupa, M.1 Br. J. Anaesth. 2000; 84 residual block after anaesthesia(propof/fent/isof)  only vecuronium but no anticholinesterase  568 consecutive patients  on admission to the recovery room. The ulnar nerve was stimulated submaximally using TOF stimulation (30 mA). Postoperative residual curarization  Messina,4 ottobre 2012,I-SIVA
  154. 154. Reboul-Marty, J.2; Larmignat, P.1; Samama, C. M.1; Cupa, M  . Of the 568 patients, 239 (42%) had a TOF <0.7 in the recovery room. These patients had received a larger cumulative dose of vecuronium than patients who had full recovery (mean 7.7 (SD 3.6) mg vs 6.2 (2.7) mg; P<0.05) and a shorter time had elapsed since the last vecuronium dose (117 (70) min vs 131 (80) min; P<0.05). Of 435 patients whose trachea was extubated, Messina,4 ottobre 2012,I-SIVA
  155. 155. Reboul-Marty, J.2; Larmignat, P.1; Samama, C. M.1; Cupa, M Messina,4 ottobre 2012,I-SIVA
  156. 156. Inadequate recovery from nm block:lieteraure data a u th o r ye a r Nm b lo c k e r Adm m ode B a illa rd 200 BJA Vecu in te rm itte nt Messina,4 ottobre 2012,I-SIVA A s s e s sm e n t:in tra o p /R R C lin ic a l/a c cel % of in a d e q re ve rs a l 42%
  157. 157. Residual block after mivacurium with or without edrophonium reversal in adults and children. Anesthesiology 1996; 84:362-7.  AB - BACKGROUND: The rapid recovery from mivacurium- induced neuromuscular block has encouraged omission of its reversal. The purpose of this study was to determine, in children and in adults, whether failure to reverse mivacurium neuromuscular block was associated with residual neuromuscular block on arrival in the postanesthesia care unit. METHODS: In 50 children, Messina,4 ottobre 2012,I-SIVA
  158. 158. Biblio da cercare     Fawcett WJ, Dash A, Francis GA, Liban JB, Cashman JN. Recovery from neuromuscular blockade: residual curarisation following atracurium or vecuronium by bolus dosing or infusions. Acta Anaesthesiol Scand 1995; 39:288-93. 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 Beemer GH, Reeves JH, Bjorksten AR. Accurate monitoring of neuromuscuiar blockade using a peripheral nerve stimulator: a review. Anaesth Intensive Care 1990; 18A90-496. Hayes AH, Mirakhur RK, Breslin DS, at al. Postoperative residual block after intermediate-acting neuromuscular blocking drugs. Anaesthesia 2001; 56:312-318. Messina,4 ottobre 2012,I-SIVA
  159. 159. Biblio sulla residual curarization             1 Williams MT, Rice 1, Ewen SP, et al. A comparison ofthe effect oftwo anaesthetic techniques on surgical conditions during gynaecological laparoscopy. Anaesthesia 2003; 58: 574-8. 2 Ptwra AI, Rorarius MG, Manninen P, et al. The costs of intense neuromuscular block for anesthesia during endolaryngeal procedures due to waiting time. Anesthesia and Analgesia 1999; 88: 1335-9. 3 Sundman E, Witt H, 01sson R, et al. The incidence and mechanisms ofpharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology 2000; 92: 977-84. 4 Eikermarm M, Vogt FM, Herbstreit F, Vahid-Dastgerdi M, Zenge MO, Ochterbeck C, de Greiff A, Peters J. The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Amj Respir Grit Med 2006: Oct 5; [Epub ahead ofprint]. 5 Eikermann M, Groeben H, FlusingJ, et al. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology 2003; 98: 1333-7. 6 Berg H, PLoed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randon-iised, and blinded study ofpostoperative pulmonary complications after atracu rium, vecuronium and pancuronium. Acta Anaesthesiologica Scandinavica 1997; 41: 1095-103. @ 2007 The Authors Journal compilation @ 2007 The Association of Anaesthetists of Great Britain and Ireland                             Anaesthesia, 2007, 62, pages 12-17 12 D. M. Maybauer et aL - Residual paralysis after cisatracurium and rocuronium 7 Hayes AH, M~rakhur RK, Breslin DS, et al. Postoperative residual block after intermediate-acting neuromuscular blocking drugs. Anaesthesia 2001; 56: 312-8. 8 Cammu G, De Witte J, De Veyider J, et al. Postoperative residual paralysis in outpatients versus inpatients. Anesthesia and Analgesia 2006; 102: 426-9. 9 Fuchs-Buder T, Hofinnockel R, Geldner G, et al. The use of neurornuscular monitoring in Germany. Anaesthesist 2003; 52: 522-6~ 10 Fuchs-Buder T, Eikermann M. Residual neuromuscular blockades Clinical consequences, frequency and avoidance strategies. Anaesthesist 2006; 55: 7-16. 11 Arain SR, Kern S, Ficke DJ, et al. Variability of duration of action of neuromuscular-blocking drugs in elderly patients. Acta Anaesthesiologica Scandinavica 2005; 49: 312-5. Sparr Hj, Beaufort TM, Fuchs-Buder T. Newer neuromuscular blocking agents: how do they compare with established agents? Drugs 2001; 61: 919-42. 13 Cammu G, de Baerdemaeker L, den Blautwen N, et al. Postoperative residual curarization with cisatracurium and rocuronium infusions. European Journal of Anaesthesiology 2002; 19: 129-34. 14 Naguib M, Samarkandi AH, Ammar A, et al. Comparative clinical pharmacology of rocuronium, cisatracurium, and their combination. Anesthesiology 1998; 89: 1116-24. @ 2007 The Authors Journal compilation C 2007 The Association of Anaesthetists of Great Britain and Ireland 15 Puhringer FK, Heier T, Dodgson M, et al. Double-blind comparison of the variability in spontaneous recovery of cisatracurium- and vecuronium-induced neuromuscular block in adult and elderly patients. Acta Anaesthesiologica Scandinavica 2002; 46: 364-71. 16 Schmith VD, Fiedler~Kelly J, Phillips L et al. Dose proportionality of cisatracurium. Journal of Clinical Pharmacology 1997; 37: 625-9. 17 van Miert MM, Eastwood NB, Boyd AH, et al. The pharmacokinetics and pharmacodynarnics of rocuronium in patients with hepatic cirrhosis. Britishjournal of Clinical Pharmacology 1997, 44: 139-44. 18 Leshe K, Sessler 131, Bjorksten AR, et al. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesthesia and Analgesia 1995; 80: 1007-14. 19 Schleppers ABM, Berry M, Bender Hj, Geldner G, Martinj. Costs analysis of anaesthesia in German hospitals in the reference year 2002. Anaesthesiologie und Intensivmedizin 2005; 46: 23-8. 20 Foster JG, Kish SK, Keenan CH. National practice with assessment and monitoring of neuromuscular blockade. Critical Care Nursing Quality 2002; 25: 27-40. Baillard C, ClecI C, Catineau J, et al. Postoperative Messina,4 ottobre 2012,I-SIVA residual neuromuscular block: a survey of management. British Journal of Anaesthesia 2005; 95: 622-6.
  160. 160. Anesth Analg. 2007 Mar;104(3):585-6. Emergency use of sugammadex after failure of standard reversal drugs.Lenz A, Hill G, White PF  .Administration of sugammadex, 350 mg IV (4 mg/kg), in the postanesthesia care unit immediately (<60 s) relieved acute respiratory distress due to residual neuromuscular blockade in a 42-yr-old patient with chronic renal failure who had received vecuronium, 10 mg IV, for tracheal intubation, after inadequate reversal of neuromuscular blockade in the operating room with neostigmine, 5 mg IV, and glycopyrrolate, 1 mg IV Messina,4 ottobre 2012,I-SIVA
  161. 161. POPC after pancuronium and atracurium(Pedersen AAS 1992;36;312-18) 12 10 8 1559 panc atrac % 6 4 1057 2 0 POPC
  162. 162. Paralisi residua Che cosa implica e come evitarla... C.Melloni Servizio Anestesia e Rianimazione Ospedale di Faenza(RA)
  163. 163. Ballard et al.Residual curarization in the recovery room after vecuronium.BJA 2000;84:394- • Incidence of residual block following vecu evaluated in the RR in 565 patients: • nerve stimulator not used and block not antagonized • RE:clinicallly significant residual block found in 42% of patients;33% extubated before the arrival in RR.
  164. 164. How to avoid residual nmblock • Do not use long acting nmb • Monitoring!!! • At a minimun,measure TOFR at the end of the case without antagonizing or before antagonizing • consider always the response to nerve stimulation together with clinical signs and symptoms…..
  165. 165. Clinical tests of postoperative neuromuscular recovery • Unreliable – sustained eye opening – tongue protrusion – arm lift to opposite shoulder – normal TV – normal or near normal VC – max insp pressure < = 25 cmH2O • Reliable – sustained head lift for 5 sec – sustained arm lift for 5 sec – sustained hand grip for 5 sec – sustained tongue depressor test – max insp press > 50 cm H2O
  166. 166. Frequency of residual curarization 45 40 35 30 % of patients 25 20 postop 15 10 5 0 Messina,4 ottobre 2012,I-SIVA panc Viby 1979 Beemer Pedersen Bevan
  167. 167. Ballard et al.Residual curarization in the recovery room after vecuronium.BJA 2000;84:394- Incidence of residual block following vecu evaluated in the RR in 565 patients:  nerve stimulator not used and block not antagonized  RE:clinicallly significant residual block found in 42% of patients;33% extubated before the arrival in RR.  Messina,4 ottobre 2012,I-SIVA
  168. 168. Is your practice different? Messina,4 ottobre 2012,I-SIVA
  169. 169. POPC after pancuronium and atracurium(Pedersen AAS 1992;36;312-18) 12 10 8 1559 panc atrac % 6 4 2 0 1057 POPC Messina,4 ottobre 2012,I-SIVA
  170. 170. Viby Mogensen et al,AAS 1997 • • • • 693 paz.randomizzati,cieco chir elettiva monitoraggio periop con Myotest e Tof confronto fra 1-5-2 ED95 di atrac,vecu,panc. • Antagonismo se necessario; • estubaz a tof eguale, tattile e resp adeguata. Messina,4 ottobre 2012,I-SIVA
  171. 171. Paralisi residua e % di tof<0.40 in RR,subito dopo trasferimento 45 40 35 30 panc atrac vecu 25 20 15 10 5 0 Tof <0.70 Messina,4 ottobre 2012,I-SIVA tof<0.40
  172. 172. Residual neuromuscular block and POPC  TOFR Panc Atrac & vecu  >0.7 4,8% 5,4%  <0.7 16,9%* 4,2% Messina,4 ottobre 2012,I-SIVA
  173. 173. Andamento temporale del tof <0.80 nella RR 50 % tof<0.80 40 panc atrac vecu 30 20 10 0 0 5 10 15 20 min Messina,4 ottobre 2012,I-SIVA 30 40 50
  174. 174. Risk of POPC following abdominal surgery 70 60 50 % 40 panc vecu & atra 30 20 10 0 20 30 40 50 age Messina,4 ottobre 2012,I-SIVA 60 70 80
  175. 175. Postoperative pulmonary complications 20 15 10 % atrac vecu panc 5 popc Messina,4 ottobre 2012,I-SIVA popc con popc blocco senza residuo blocco residuo 0 panc vecu atrac
  176. 176. Popc secondo il tipo di chirurgia 16 14 12 10 addom ortop ginecol % 8 6 4 2 0 Messina,4 ottobre 2012,I-SIVA popc
  177. 177. Fattori di rischio per POPC nello studio AAS 1997  Tipo di chirurgia;freq * 2-10(addominale)  età:ogni 10 anni * 1.68  durata di anestesia(> o < 200 min)*3.3  panc e tof<0.70:*5 Messina,4 ottobre 2012,I-SIVA
  178. 178. How to avoid residual nmblock Do not use long acting nmb  Monitoring!!!  At a minimun,measure TOFR at the end of the case without antagonizing or before antagonizing  consider always the response to nerve stimulation together with clinical signs and symptoms…..  Messina,4 ottobre 2012,I-SIVA
  179. 179. Clinical tests of postoperative neuromuscular recovery  Unreliable » sustained eye opening » tongue protrusion » arm lift to opposite shoulder » normal TV » normal or near normal VC » max insp pressure < = 25 cmH2O Messina,4 ottobre 2012,I-SIVA  Reliable » sustained head lift for 5 sec » sustained arm lift for 5 sec » sustained hand grip for 5 sec » sustained tongue depressor test » max insp press > 50 cm H2O
  180. 180. 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.  Messina,4 ottobre 2012,I-SIVA
  181. 181. Time from neostigmine administration to TOFR 0.70 25,00 20,00 low max min mediana 15,00 10,00 5,00 0,00 I twitch II twitch Messina,4 ottobre 2012,I-SIVA III twitch IV twitch
  182. 182. Time from neostigmine administration to TOFR 0.80 80 70 60 low max min mediana 50 40 30 20 10 0 I twitch II twitch Messina,4 ottobre 2012,I-SIVA III twitch IV twitch
  183. 183. Time from neostigmine administration to TOFR 0.90 80 70 60 low max min mediana 50 40 30 20 10 0 I twitch II twitch Messina,4 ottobre 2012,I-SIVA III twitch IV twitch
  184. 184. MMG magnitude of the first TOF twitch(T1) measured at the reappearance of each of the 4 tactile TOF responses. 80 70 T1 % 60 low max min mediana 50 40 30 20 10 0 I twitch II twitch Messina,4 ottobre 2012,I-SIVA III twitch IV twitch
  185. 185. 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. Messina,4 ottobre 2012,I-SIVA
  186. 186. 17 O'Hara DA, Fragen RJ, Shanks CA. Comparison of visual and measured train-of-four recovery after vecuronium-induced neuromuscular blockade using two anaesthetic techniques. Br J Anaesth 1986; 58:1300-1302.  18 Kopman AF. Tactile evaluation of train-of-four count as an indicator of  Messina,4 ottobre 2012,I-SIVA
  187. 187.  31 Eikermann M, Groeben H, Peters J. Prediction of the effects of partial neuromuscular blockade on pulmonary function by accelerography and mechanomyography of adductor pollicis muscle [Abstract]. Anesthesiology 2001; 95:A1021. Messina,4 ottobre 2012,I-SIVA
  188. 188. Messina,4 ottobre 2012,I-SIVA
  189. 189. Valutazione del blocco residuo  Valutazione della ripresa neuromuscolare: » prima del risveglio: – valutazione della forza contrattile in risposta alla stimolazione:MMG,EMG.accelerometria,qualitative e quantitative:TOF,DBS,tetano 50,100 HZ…….; – TV,RR,forza insp ed esp » dopo il risveglio,volontarietà: – sollevamento testa> 5 sec – sollevamento braccio – stretta di mano – protrusione lingua Messina,4 ottobre 2012,I-SIVA – apertura ampia occhi
  190. 190. 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  Messina,4 ottobre 2012,I-SIVA
  191. 191. Clinical signs of residual weakness vs tof at the AP(Kopman,Anesthesiology,1997;86:765-71) 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 head lift leg lift retain tongue depressor lowest tof highest tof at which test passed or failed Messina,4 ottobre 2012,I-SIVA
  192. 192.  In summary, our data show that after repeated administration, the duration of action and its variability are greater with rocuronium than with cisatracurium. These pharmacodynamic differences do not necessarily translate into a higher incidence of residual paralysis, because clinicians who monitor neuromuscular transmission can balance some effects of the greater duration of action and variability of rocuronium by terminating repeated NBD administration earlier. Cisatracurium may, however, have some clinically relevant advantages when NB is required for long-term (major) surgery, particularly when anaesthetists do not monitor neuromuscular function. Messina,4 ottobre 2012,I-SIVA
  193. 193. Ipossia Chemrorecet perif ipercapnia Chemrecett.centr SNC Messina,4 ottobre 2012,I-SIVA iperventilazione
  194. 194. nmb Sito nicotinico ipossia Corpi carotidei Sito muscari nico Messina,4 ottobre 2012,I-SIVA atropina
  195. 195. Messina,4 ottobre 2012,I-SIVA
  196. 196. Messina,4 ottobre 2012,I-SIVA
  197. 197. Conclusioni  Esiste evidenza sperimentale e clinica che i nmb nondepolarizzanti inteferiscano con il controllo della ventilazione in condizioni di ipossia,verosimilmente attraverso una depressione reversibile della attività chemorecettoriale dei corpi carotidei implicazioneclinica Messina,4 ottobre 2012,I-SIVA
  198. 198. Sugammadex efficace anche in blocco profondo alla ricomparsa di T2 • sugammadex given as a reversal agent at the reappearance of T2 was effective in reversing neuromuscular block induced by either rocuronium (0.60 mg/kg) or vecuronium (0.10 mg/kg) in patients with an American Society of Anesthesiologists physical status of I or II. Cholinesterase inhibitors are only effective in reversing neuromuscular block if given when partial spontaneous recovery has already occurred.17 • The present study showed that sugammadex was effective as a reversal agent for both rocuronium- and vecuronium- induced block when given at such a depth of block i.e., the reappearance of T2.18
  199. 199. •Nessun effetto collaterale
  200. 200. • • • • • Expert Opin Pharmacother. 2008 May;9(8):1375-86. Links Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia. Donati F. University of Montréal, Hôpital Maisonneuve-Rosemont, Department of Anesthesiology, 5415, boul l'Assomption, Montréal, Québec, H1T 2M4, Canada. francois.donati@umontreal.ca BACKGROUND: Neuromuscular blocking agents are used to provide relaxation and immobility during surgery. To avoid residual paralysis after anaesthesia, reversal of blockade is commonly accomplished with anticholinesterase agents but these drugs have cardiovascular side effects and incomplete effectiveness. Sugammadex is a cyclodextrin that binds rocuronium and chemically similar neuromuscular blocking drugs. OBJECTIVE: Published data on the effectiveness of sugammadex as a reversal agent were examined. METHODS: Peer-reviewed articles on residual postoperative paralysis and sugammadex (ORG 25969) were analysed. RESULTS: Rocuronium-sugammadex complexes are formed and excreted via the kidney. The dissociation constant of the reaction is estimated at 0.1 microM. Sugammadex produces more rapid reversal of rocuronium- and vecuronium-induced blockade than current reversal agents. The dose required depends directly on intensity of blockade. To date, there appear to be few side effects. Inadequate dosage may lead to reparalysis. CONCLUSION: More data are needed, especially in patients with renal failure and those who require neuromuscular blockade again soon after receiving sugammadex.
  201. 201. • • • • • Br J Anaesth. 2008 May;100(5):622-30. Epub 2008 Apr 2. Links Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine. Flockton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L, Giunta FG, Meistelman C, Prins ME. University Department of Anaesthesia, School of Clinical Sciences, Duncan Building, Daulby Street, Liverpool L69 3GA, UK. lizzy@lizzyflockton.fsnet.co.uk BACKGROUND: Reversal of the residual effect of rocuronium or cisatracurium by neostigmine may be slow and associated with side-effects. This randomized, safety-assessor-blinded study compared the efficacy of sugammadex, a selective relaxant binding agent for reversal of rocuronium-induced neuromuscular block, with that of neostigmine for reversal of cisatracurium-induced neuromuscular block. The safety of sugammadex and neostigmine was also evaluated. METHODS: Adult surgical patients (ASA class I-III) were randomized to sugammadex 2.0 mg kg(-1) for reversal of block induced by rocuronium 0.6 mg kg(-1), or neostigmine 50 microg kg(-1) for reversal of block induced by cisatracurium 0.15 mg kg(-1). Anaesthesia was induced and maintained using i.v. propofol and remifentanil, fentanyl, or sufentanil. Neuromuscular function was monitored using acceleromyography (TOF-Watch SX). Sugammadex or neostigmine was administered at reappearance of T(2). The primary efficacy variable was time for recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Eighty-four patients were randomized, 73 of whom received sugammadex (n=34) or neostigmine (n=39). Time from start of administration of reversal agent to recovery of the TOF ratio to 0.9 was 4.7 times faster with sugammadex than with neostigmine (geometric mean=1.9 vs 9.0 min, P<0.0001). Reversal of block was sustained in all patients. There were no serious adverse effects from either reversal agent and no significant changes in any measure of safety, except for similar elevations in urinary N-acetyl glucosaminidase in both groups. CONCLUSIONS: Sugammadex 2.0 mg kg(-1) administered at reappearance of T(2) was significantly faster in reversing rocuronium-induced blockade than neostigmine was in reversing cisatracurium-induced block.
  202. 202. neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine. Br J Anaesth. 2008 ;100:622- . 30 • Tiva propofol /remifentanil o sufentanil • Alla ricomparsa del T2 • Rocuronium 0.6 mg/kg antagonizzato con sugammadex 2 mg/kg • Cisatracurium 0.15 mg/kg antagonizzato con neostigmnma 50 microgr/kg • Tempo di ritorno del Tofr 0.9:1.9 min dopo sugammadex,9 min dopo neostigmina
  203. 203. • : Can J Anaesth. 2008 Feb;55(2):124-5; author reply 125-6. Links • Comment on: Can J Anaesth. 2007 Sep;54(9):689-95. Non-steroidal neuromuscular blocking agents to reestablish paralysis after reversal of rocuroniuminduced neuromuscular block with sugammadex. • de Boer HD, Driessen JJ, van Egmond J, Booij LH.
  204. 204. • • • • • 1: J Pharmacokinet Pharmacodyn. 2007 Dec;34(6):771-88. Epub 2007 Sep 21. Links Simulation of the reversal of neuromuscular block by sequestration of the free molecules of the muscle relaxant. Nigrovic V, Bhatt SB, Amann A. Department of Anesthesiology, College of Medicine, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA. vladimir.nigrovic@utoledo.edu The study examined in simulations the interaction between a muscle relaxant and an antagonist that binds the free molecules of the relaxant, as experimentally demonstrated for rocuronium and sugammadex. The hypothetical muscle relaxant D and the hypothetical antagonist X were assigned pharmacokinetic properties to define the time course of their concentrations in plasma, and pharmacodynamic properties to define binding of D to either X or the receptors at the motor end plates. D, X, and their complex DX were postulated to diffuse between plasma and the effect compartment. The first and the fourth twitch elicited in sequential trains of four stimuli were evaluated in a model of neuromuscular transmission. The rates of reactions were formulated as differential equations and the equations solved numerically. If the affinity of D for X is comparable to that of D for the postsynaptic receptors, doses of X two to four times larger than the dose of D produce a fast and a complete recovery of the twitches. Smaller doses of X or lower affinities of D for X accomplish a slower and only partial recovery. Additionally, the complete restoration of twitch strength within 2 min after the injection of X requires that X and DX diffuse into the effect compartment. The simulations reveal the physicochemical, pharmacokinetic, and pharmacodynamic properties of an antagonist that restores twitch strength by sequestering the free molecules of the muscle relaxant.
  205. 205. • • • • • : Anesthesiology. 2007 Aug;107(2):239-44. Links Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study. de Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M. Department of Anesthesiology, Radboud University Medical Center Nijmegen, The Netherlands. pm.mertes@chu-nancy.fr BACKGROUND: Reversal of rocuronium-induced neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a modified gamma-cyclodextrin derivative. This study investigated the efficacy and safety of sugammadex in reversing rocuronium-induced profound neuromuscular blockade at 5 min in American Society of Anesthesiologists physical status I and II patients. METHODS: Forty-five American Society of Anesthesiologists physical status I and II patients (aged 18-64 yr) scheduled to undergo surgical procedures (anticipated anesthesia duration >/= 90 min) were randomly assigned to a phase II, multicenter, assessor-blinded, placebo-controlled, parallel, dose-finding study. Anesthesia was induced and maintained with propofol and an opioid. Profound neuromuscular blockade was induced with 1.2 mg/kg rocuronium bromide. Sugammadex (2.0, 4.0, 8.0, 12.0, or 16.0 mg/kg) or placebo (0.9% saline) was then administered 5 min after the administration of rocuronium. Neuromuscular function was monitored by acceleromyography, using train-of-four nerve stimulation. Recovery time was the time from the start of administration of sugammadex or placebo, to recovery of the train-of-four ratio to 0.9. Safety assessments were performed on the day of the operation and during the postoperative and follow-up period. RESULTS: A total of 43 patients received either sugammadex or placebo. Increasing doses of sugammadex reduced the mean recovery time from 122 min (spontaneous recovery) to less than 2 min in a dose-dependent manner. Signs of recurrence of blockade were not observed. No serious adverse events related to sugammadex were reported. Two adverse events possibly related to sugammadex were reported in two patients (diarrhea and light anesthesia); however, both patients recovered without sequelae. CONCLUSIONS: Sugammadex rapidly and effectively reversed profound rocuronium-induced neuromuscular blockade in humans and was well tolerated.
  206. 206. Antagonismo immediato di un blocco profondo H, Heeringa M, Klimek M. de Boer HD, Driessen JJ, Marcus MA, Kerkkamp Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study. Anesthesiology. 2007 ;107:239-44. • Rocuronium 1.2 mg/kg • Dopo 5 min • placebo o sugammadex 2.0, 4.0, 8.0, 12.0,16.0 mg/kg • TOFR 0.9 <2 min dopo sugammadex,122 min dopo placebo
  207. 207. • Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J, Skovgaard LT,Krintel JJ: Residual neuromuscular block is a risk factor for postoperative pulmonary complications: A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand 1997; 41:1095–103 • 2. Arbous MS, Meursing AE, van Kleef JW, de Lange JJ, Spoormans HH, Touw • P, Werner FM, Grobbee DE: Impact of anesthesia management characteristics on
  208. 208. • • • • • : Anesthesiology. 2007 Aug;107(2):239-44. Links Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study. de Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M. Department of Anesthesiology, Radboud University Medical Center Nijmegen, The Netherlands. pm.mertes@chu-nancy.fr BACKGROUND: Reversal of rocuronium-induced neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a modified gamma-cyclodextrin derivative. This study investigated the efficacy and safety of sugammadex in reversing rocuronium-induced profound neuromuscular blockade at 5 min in American Society of Anesthesiologists physical status I and II patients. METHODS: Forty-five American Society of Anesthesiologists physical status I and II patients (aged 18-64 yr) scheduled to undergo surgical procedures (anticipated anesthesia duration >/= 90 min) were randomly assigned to a phase II, multicenter, assessor-blinded, placebo-controlled, parallel, dose-finding study. Anesthesia was induced and maintained with propofol and an opioid. Profound neuromuscular blockade was induced with 1.2 mg/kg rocuronium bromide. Sugammadex (2.0, 4.0, 8.0, 12.0, or 16.0 mg/kg) or placebo (0.9% saline) was then administered 5 min after the administration of rocuronium. Neuromuscular function was monitored by acceleromyography, using train-of-four nerve stimulation. Recovery time was the time from the start of administration of sugammadex or placebo, to recovery of the train-of-four ratio to 0.9. Safety assessments were performed on the day of the operation and during the postoperative and follow-up period. RESULTS: A total of 43 patients received either sugammadex or placebo. Increasing doses of sugammadex reduced the mean recovery time from 122 min (spontaneous recovery) to less than 2 min in a dose-dependent manner. Signs of recurrence of blockade were not observed. No serious adverse events related to sugammadex were reported. Two adverse events possibly related to sugammadex were reported in two patients (diarrhea and light anesthesia); however, both patients recovered without sequelae. CONCLUSIONS: Sugammadex rapidly and effectively reversed profound rocuronium-induced neuromuscular blockade in humans and was well tolerated.
  209. 209. • • • • • 1: Pharmacotherapy. 2007 Aug;27(8):1181-8. Links Sugammadex: a novel agent for the reversal of neuromuscular blockade. Nicholson WT, Sprung J, Jankowski CJ. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. nicholson.wayne@mayo.edu To achieve spontaneous ventilation after completion of surgery, the nondepolarizing effects on skeletal muscle relaxation are often reversed by administration of an acetylcholinesterase inhibitor. However, these agents increase acetylcholine at both the neuromuscular junction and the muscarinic receptors. Therefore, coadministration of an anticholinergic agent is required to prevent parasympathetic adverse effects. In addition, a relative pharmacologic ceiling effect is seen with inhibition of acetylcholinesterase, necessitating some recovery of neuromuscular function before an acetylcholinesterase inhibitor is administered. Sugammadex is a new modified gamma-cyclodextrin compound under clinical investigation in the United States. It does not interact with cholinergic mechanisms to elicit reversal. Instead, it is a selective relaxant binding agent and acts by forming a 1:1 complex with steroidal nondepolarizing neuromuscular blockers in the plasma, lowering the effective concentration available at the receptor. Due to its selectivity, sugammadex does not inhibit the effects of nondepolarizing agents of the benzylisoquinolinium class. In contrast to acetylcholinesterase inhibition, sugammadex is effective even when administered during profound blockade, and it does not require coadministration of an anticholinergic agent. It provides a novel mechanism of action for reversal of the neuromuscular block induced by nondepolarizing aminosteroidal agents.
  210. 210. • • • • • • 1: Anesthesiology. 2007 May;106(5):935-43. Links Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM. Department of Anesthesiology and Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria. harald.sparr@dornbirn.at BACKGROUND: Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy, safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were evaluated. METHODS: Ninety-eight male adult patients were randomly assigned to receive sugammadex (1, 2, 4, 6, or 8 mg/kg) or placebo at 3, 5, or 15 min after 0.6 mg/kg rocuronium. Patients were anesthetized with propofol and fentanyl. The primary endpoint of the study was the time to achieve a recovery of train-of-four ratio to 0.9. Neuromuscular blockade was measured using acceleromyography. Concentrations of rocuronium and sugammadex were determined in venous blood and urine samples. A population pharmacokinetic model using NONMEM (GloboMax LLC, Hanover, MD) was applied. RESULTS: The mean time to recovery of the train-of-four ratio to 0.9 after dosing at 3, 5, and 15 min decreased from 52.1, 51.7, and 35.6 min, respectively, after administration of placebo to 1.8, 1.5, and 1.4 min, respectively, after 8 mg/kg sugammadex. Sugammadex was safe and well tolerated. However, 20.4% of patients showed signs of inadequate anesthesia after its administration. The median cumulative excretion of rocuronium in the urine over 24 h was 26% in the placebo group and increased to 58-74% after 48 mg/kg sugammadex. The mean plasma clearances of sugammadex and rocuronium were 0.084 and 0.26 l/min, respectively. CONCLUSIONS: In male subjects, sugammadex safely reversed profound neuromuscular blockade induced by 0.6 mg/kg rocuronium in a dose-dependent manner. Sugammadex enhanced the renal excretion of rocuronium, and its clearance is approximately one third that of rocuronium. PMID: 17457124 [PubMed - indexed for MEDLINE]
  211. 211. Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics Anesthesiology. 2007 ;106:935-43 • Propofol/fentanyl anestesia • Rocuronium 0.6 mg/kg • Sugammadex 1,2,4,6,8 mg/kg o placebo dopo 3,5,o 15 min
  212. 212. Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics Anesthesiology. 2007 ;106:935-43.
  213. 213. • Br J Anaesth. 2007 May;98(5):624-7. Epub 2007 Mar 8. Links • Reversal of rocuronium-induced (1.2 mg kg-1) profound neuromuscular block by accidental high dose of sugammadex (40 mg kg-1). • Molina AL, de Boer HD, Klimek M, Heeringa M, Klein J. • Department of Anaesthesiology, Erasmus University Medical Centre, Rotterdam, and Martini Hospital Groningen, The Netherlands. • Sugammadex is the first selective relaxant binding agent and reverses rocuronium-induced neuromuscular block. A case is reported in which a patient accidentally received a high dose of sugammadex (40 mg kg-1) to reverse a rocuronium-induced (1.2 mg kg-1) profound neuromuscular block. A fast and efficient recovery from profound neuromuscular block was achieved and no adverse events or other safety concerns were reported.
  214. 214. • 1: Anesth Analg. 2007 Mar;104(3):585-6. Links • Comment in: Anesth Analg. 2007 Sep;105(3):876-7; author reply 878. Anesth Analg. 2007 Sep;105(3):876; author reply 876, 878. Anesth Analg. 2007 Sep;105(3):877-8; author reply 878. Anesth Analg. 2007 Sep;105(3):877; author reply 878. Emergency use of sugammadex after failure of standard reversal drugs. • Lenz A, Hill G, White PF. • Department of Anesthesiology and Pain Management; University of Texas Southwestern Medical Center, Dallas, Texas 75390-9068, USA. • Administration of sugammadex, 350 mg IV (4 mg/kg), in the postanesthesia care unit immediately (<60 s) relieved acute respiratory distress due to residual neuromuscular blockade in a 42-yr-old patient with chronic renal failure who had received vecuronium, 10 mg IV, for tracheal intubation, after inadequate reversal of neuromuscular blockade in the operating room with neostigmine, 5 mg IV, and glycopyrrolate, 1 mg IV.
  215. 215. • • • • • : Anesth Analg. 2007 Mar;104(3):582-4. Links A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex. Eleveld DJ, Kuizenga K, Proost JH, Wierda JM. Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Medical Center, University of Groningen, Groningen, The Netherlands. d.j.eleveld@anest.umcg.nl BACKGROUND: We present a case in which a temporary decrease in train-of-four (TOF) response was observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9 mg/kg of rocuronium. At the end of the operation, the TOF ratio was >0.9, and the patient woke normally, without signs of muscle weakness. We describe this temporary decrease in muscle response during muscle relaxation reversal as muscle relaxation rebound and hypothesize that it occurs when the dose of sugammadex is sufficient for complex formation with rocuronium in the central compartment, but insufficient for redistribution of rocuronium from peripheral to central compartments. METHODS: To investigate our hypothesis, we developed and fit a simple pharmacokinetic- pharmacodynamic model of rocuronium, sugammadex, and their interaction to the patient TOF response data. RESULTS: Simulations using the fitted model indicate that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. CONCLUSIONS: Sufficiently large doses of sugammadex eliminate the possibility for muscle relaxation rebound, which does not require dissociation of the sugammadex/ rocuronium complex.
  216. 216. Sacan O, White PF, Tufanogullari B, Klein KSugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg. 2007 ;104:569-74. • • • . Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9068, USA. BACKGROUND: Sugammadex is a modified [gamma] cyclodextrin compound, which encapsulates rocuronium to provide for a rapid reversal of residual neuromuscular blockade. We tested the hypothesis that sugammadex would provide for a more rapid reversal of a moderately profound residual rocuronium-induced blockade than the commonly used cholinesterase inhibitors, edrophonium and neostigmine. METHODS: Sixty patients undergoing elective surgery procedures with a standardized desflurane-remifentanil-rocuronium anesthetic technique received either sugammadex, 4 mg/kg IV (n = 20), edrophonium, 1 mg/kg IV and atropine, 10 microg/kg IV (n = 20), or neostigmine, 70 microg/kg IV and glycopyrrolate, 14 microg/kg IV (n = 20) for reversal of neuromuscular blockade at 15 min or longer after the last dose of rocuronium using acceleromyography to record the train-of-four (TOF) responses. Mean arterial blood pressure and heart rate values were recorded immediately before and for 30 min after reversal drug administration. Side effects were noted at discharge from the postanesthesia care unit. RESULTS: The three groups were similar with respect to their demographic characteristics and total dosages of rocuronium prior to administering the study medication. Although the initial twitch heights (T1) at the time of reversal were similar in all three groups, the time to achieve TOF ratios of 0.7 and 0.9 were significantly shorter with sugammadex (71 +/- 25 and 107 +/- 61 s) than edrophonium (202 +/- 171 and 331 +/- 27 s) or neostigmine (625 +/- 341 and 1044 +/- 590 s). All patients in the sugammadex group achieved a TOF ratio of 0.9 < or =5 min after reversal administration compared with none and 5% in the edrophonium and neostigmine groups, respectively. Heart rate values at 2 and 5 min after reversal were significantly higher in the neostigmine-glycopyrrolate group compared with that in sugammadex. Finally, the incidence of dry mouth was significantly reduced in the sugammadex group (5% vs 85% and 95% in the neostigmine and edrophonium groups, respectively). CONCLUSION: Sugammadex, 4 mg/kg IV, more rapidly and effectively reversed residual neuromuscular blockade when compared with neostigmine (70 microg/kg IV) and edrophonium (1 mg/kg IV). Use of sugammadex was associated with less frequent dry mouth than that with the currently used reversal drug combinations.
  217. 217. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophoniumatropine sugammadex, 4 mg/kg edrophonium, 1 mg/kg IV and atropine, 10 microg/kg Neostimine 70 microgr/Kg, and glycopirrolate 14 microg/kg Tofr 0.7 71 +/- 25 202 +/- 171 s 625 +/- 341 s Tofr 0.9 107 +/- 61 s 331 +/- 27 1044 +/- 590 s) Tofr 0.9 <5 min all none 5%

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