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  • 1. C’è qualche cosa di nuovo nel campo della miorisoluzione??? Claudio Melloni Servizio Anestesia e Rianimazione Ospedale di Faenza(RA) Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 2. PORC: Post Operative Residual Curarization ! I Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 3. Frequency of residual curarization 45 40 35 30 % of patients 25 postop 20 15 10 5 0 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) panc Viby 1979 Beemer Pedersen Bevan
  • 4. 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. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 5. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 6. Residual neuromuscular block and POPC TOFR Panc Atrac & vecu >0.7 4,8% 5,4% <0.7 16,9%* 4,2% Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 7. Andamento temporale del tof <0.80 nella RR % tof<0.80 50 40 panc atrac vecu 30 20 10 0 0 5 10 15 20 min Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) 30 40 50
  • 8. Risk of POPC following abdominal surgery 70 60 50 % 40 panc vecu & atra 30 20 10 0 20 30 40 50 60 age Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) 70 80
  • 9. Popc secondo il tipo di chirurgia 16 14 12 10 addom ortop ginecol % 8 6 4 2 0 popc Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 10. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 11. Postoperative pulmonary complications 20 15 10 % atrac vecu panc 5 popc popc con popc blocco senza residuo blocco residuo Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) 0 panc vecu atrac
  • 12. Kopman et al.Relationship of the train of four fade ratio to clinical signes and symptoms of residual paralysis in awake volunteers.Anesthesiology,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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 13. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 14. 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?? 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) head lift leg lift retain tongue depressor lowest tof highest tof at which test passed or failed
  • 15. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 16. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 17. 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 applica ad una ampia gamma di situazioni cliniche. Esistono pesanti pressioni economiche per la diminuzione della spesa sanitaria. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 18. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 19. Conclusions form Kopman,Brull,Erikkson….. indicators of recovery of nm function should be changed. The TOF ratio <0.9 was also associated with functional impairment of the pharynx and upper correlated volunteers' subjective feelings of partial neuromuscular weakness with the clinical counterpart of neuromuscular recovery. All subjects had significant signs and symptoms of residual paralysis at a TOF ratio of 0.7 and satisfactory recovery of neuromuscular function after mivacuriuminduced neuromuscular block required return of the TOF ratio to >0.9 . According to these studies, the absence of muscle relaxantinduced clinical effects may be defined as the return to a TOF ratio ³0.9 at the AP. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 20. Kim KS, Lew SH, Cho HY, Cheong MA. Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine.Anesth Analg. 2002 95:1656-60 Estubazione nel 94% dei paz. prima di entrare nella RR 125/602 Vecu>rocu 125/602 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 21. Fattori di rischio di PORC (Kim et al.Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine.Anesth Analg. 2002 95:1656-60 ) Dose cumulativa di vecu maggiore Più breve distanza dall’ultima iniezione Paz con blocco residuo più ipotermici Sollevamento testa> 5 sec più sensibile della depressione della lingua? Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 22. McCaul, C.; Tobin, É.; Boylan, J. F.; McShane, A. J.* Atracurium is associated with postoperative residual curarization.BJA 2002;89:766-769 65% patients TOFR <0.7 at extubation Risk factors: » shorter procedures » more profound neuromuscular block at the time of neostigmine administration » shorter time intervals from administration of last dose of atracurium to administration of antagonist » Shorter times from administration of antagonist to extubation » TOFR at the time of antagonism was positively correlated with time elapsed since last dose of atracurium 19 patients had clinical evidence of impaired neuromuscular function as evidenced by a total of 40 clinical events: » » » » » . uncoordinated movements oxygen desaturation upper airway obstruction ptosis diplopia/blurring of vision. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 23. McCaul, C.; Tobin, É.; Boylan, J. F.; McShane, A. J.* Atracurium is associated with postoperative residual curarization.BJA 2002;89:766-769 » A peripheral nerve stimulator was used in 50% (20/40) of patients. » Trainees who did not use nerve stimulators were more experienced than those who did [6.3 (0.8) vs 4.5 (0.4) yr, P=0.04]. » Use of nerve stimulators was not associated with altered atracurium dosage, depth of blockade before antagonism, time interval from antagonism of neuromuscular block to tracheal extubation, or incidence of PORC. The sole multivariate predictor of residual neuromuscular block was duration of surgical procedure, which correlated inversely with PORC Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 24. Dilly M P,Plaud B.,Thery V, Debaene B.Incidence of residual neuromuscular block in the PACU after a single intubating dose of intermediate duration muscvle relaxant.BJA 1999;82 suppl 1. 526 patients single intubating dose 2ED 95 of vecuronium, rocuronium or atracurium. a clinical evaluation and a qualitative measurement of the TOF count were performed At the admission in the PACU, TOF ratio at the AP was measured using an accelerometry method (TOFWatch, Organon Tecknica). TOFR< 70% in 16,2%;TOFR< 90% in 44,9%. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 25. Dilly et al.Incidence of residual neuromuscular block in the PACU after a single intubating dose of intermediate duration muscvle relaxant.BJA 1999;82 suppl 1. 2 hrs after the a single intubating dose (2 x ED95) of non-depolarizing MR of intermediate duration (n = 238), 10% of the patients had a TOFR< 70% +TOFR< 90% in 36,6% of the cases. Conclusions: The incidence of RNMB two hours after a single dose (2 x DA95) of MR of intermediate duration is about 36% (TOF ratio <90%) These results argue for a quantitative measurement of the TOF using accelerometry to assess residual paralysis in the PACU. This measurement needs to be performed even after the administration of a single dose of non-depolarizing MR, and whatever the duration of the anesthetic procedure. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 26. Cammu G, de Baerdemaeker L, den Blauwen N, de Mey JC, Struys M, Mortier E. Postoperative residual curarization with cisatracurium and rocuronium infusions.Eur J Anaesthesiol. 2002;19:129-34. Chir maggiore di durata 3-4 h Infusioni terminate all’inizio della sutura cutanea Monitoraggio nm:EMG Datex;tof ogni min Anestesia mant:propofol/sufent Miorisoluz mant al 10% di T1 Estubaz a TOF 0.90 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 27. Cammu et al. Postoperative residual curarization with cisatracurium and rocuronium infusions.Eur J Anaesthesiol. 2002;19:129-34. 70 60 50 % o min Cisatrac 40 Rocuronium 30 20 10 0 Tof medio fine chir neostigm in tof at reversal Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) tempo fine chir-tof 0.90 fine chirestubaz
  • 28. PR. Freund KL Posner, DJ. Dalgleish. Decrease in Emergent Reintubation after Establishing a Standard for Monitoring and Documenting Reversal of Neuromuscular Blockade .Anesthesiology 2002 ;96:A1125 : There is no ASA standard for documentation of adequate return of neuromuscular (NM) function. Our continuous quality improvement program1 identified several cases of emergent reintubation for inadequate return of NM function. We hypothesized that setting a standard for confirming and documenting return of NM function would decrease the incidence of emergent reintubation in PACU. Methods: After IRB approval, 100 consecutive records for open intra-abdominal surgery were retrospectively reviewed (baseline). Adequate documentation was defined as a note of any one of commonly used criteria for return of NM function: no fade on train of four, sustained tetanic contraction at 50Hz for 5 seconds, or negative inspiratory force > -35cm H2O. Inadequate documentation was defined as mention of any one criteria without documentation of adequacy (e.g., note of train of four without mention of fade or sustained tetanus). A departmental educational program of lectures plus a written and email bulletin explaining the service standards for monitoring the return of NM function was then implemented. A 2nd set of 100 consecutive records was examined over a five week intervention period. Inadequate documentation during this period prompted a verbal or electronic reminder to the primary care giver. After an interlude of 2 months without reminders, a final consecutive 100 records were reviewed (post intervention). Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 29. Freund et al.. Decrease in Emergent Reintubation after Establishing a Standard for Monitoring and Documenting Reversal of Neuromuscular Blockade.Anesthesiology 2002 ; 96:A1125 Results: During the baseline period, only 13% of records had adequate documentation and 40% had no documentation at all (Figure). In the post intervention period, compliance with the service standard was 50% (Figure). During the baseline period, 4% of anesthetics administered by residents and 31% of those by CRNAs had adequate documentation, increasing to 57% for the residents and 44% for the CRNAs in the post interventionperiod. There were no emergent reintubations in the PACU during the study period. Discussion: Our CQI system identified a problem with emergent reintubation in the PACU. Initial chart review confirmed inadequate documentation of the return of NM function after the use of NM blocking drugs. The educational program has improved documentation and emergent reintubations in our PACU have decreased. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 30. Effetti di un programma di incentivazione qualitativa sulla annotazione diligente della ripresa della funzione nm. (chir.add.) Letture Bollettino scritto E mail 60 50 40 % delle cartelle 30 adeguata inadeguata senza documentazione 20 10 0 baseline intervento Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) post intervento
  • 31. NEW DRUGS Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 32. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 33. White PF .Rapacuronium:why did it fail as a replacement for succinylcholine? Br.J.Anaesth.2002;88;163-65 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 34. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 35. TETRAIDROCHINOLINA CLOROFUMARATO Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 36. Belmont MR. Lien C A, Savarese , Patel S,Fischer G,Mook R.Neuromuscular blocking effects of GW280430A at the adductor pollicis and larynx in human.BJA 1999;82:suppl A 419 20 pts Midaz/fent/propofol N2O/O2/propofol infusion+ fent qb. IOT senza mioriiassanti Monitoraggio: » forza all’AP » pressione cuffia del ETT con stimolaz transcutanea sulla faccia lat della tiroide. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 37. GW280340A The structure of this mixed-tetrahydroisoquinolinium chlorofumarate is given in . The similarity in structure to mivacurium is demonstrated. The presence of three methyl groups between the quaternary nitrogen and oxygen atom at each end of the carbon chain suggests that, similar to mivacurium, this compound will not undergo Hofmann degradation. Little is known as yet about its metabolism. It is said to be degraded by chemical mechanisms in vitro. It is possible that the chloride substituted double bond in the carbon chain is its weak point. The molecule appears to be in the trans—trans configuration similar to one of the active isomers of mivacurium and in contrast to cisatracurium. It is the trans isomers of mivacurium and atracurium that undergo ester hydrolysis. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 38. GW280430A:tetraidrochinolinio clrofumarato 1 ED95:0.18 mg/kg 15 10 AP Larynx onset 25%rec 75% rec 95% rec Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) 25-75% T4:T1 0.9 rec Larynx 0 AP 5
  • 39. GW280430A 2 ED 95:0.36 mg/kg 15 Larynx 10 AP 5 0 AP onset 25%rec 75% rec 95% rec 25-75% rec T4:T1 0.9 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) Larynx
  • 40. GW280430A 3 ED 95:0.54 mg/kg 20 15 Larynx 10 5 0 AP onset 25%rec 75% rec 95% rec 25-75% T4:T1 rec 0.9 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) AP Larynx
  • 41. Belmont,Lien.... Asa abstracts 2003.GW280430A,now 430A 40 ASA 1 ,male and female volunteers, aged 18-50, Anesthesia: midazolam, fentanyl, propofol: maintained with an infusion of propofol and N2O 70%/O2 30%. ulnar nerve was stimulated at the wrist with a train-of-four (TOF) every 10 seconds and MMG responses were recorded from the adductor pollicis. data were analyzed for onset of maximum block and recovery times. ED95 calculated from the first 15 volunteers' doses, and accounting for TOF monitoring, is approximately 0.125mg/kg Mean onsets decreased from 122 to 54 seconds for doses ranging from 1.5 to 7XED95. Mean total durations, 95%T1 recovery, were 10.9-15.9 minutes for these doses. Mean clinical durations, 25%T1 recovery, ranged from 3.5 to 9.8 minutes No fasciculations were observed and fade of TOF during recovery was noted. Cardiovascular changes observed through the 5XED95 dose were minimal (<20%), and rare. Conclusions: 430A is a potent non-depolarizing neuromuscular blocking agent with a rapid onset and an ultra-short duration of action. Further study of this experimental compound di Anestesia e Rianimazione Ospedale di Faenza(RA) is warranted. Servizio
  • 42. Farmacodinamica del GW430A ;da Belmont,Lien.... Asa abstracts 2003. GW 430A 140 120 100 80 60 40 20 0 sec 0,19 0,25 0,375 0,625 0,825 min onset T125% Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) T1 95%
  • 43. Lien CA et al.Pharmacodynamics of spontaneous and edrophonium facilitated recovery following administration of GW 430A.Anesthesiology 2003;A1154 12 10 8 min 0,25 0,375 0,625 0,825 6 4 2 0 T125% T1 25% dopo RI 25-75% Servizio di Anestesia e Rianimazioneedroph Faenza(RA) Ospedale di RI 25-75% dopo edroph RI 5-95%
  • 44. BISTROPINIL DIESTERE Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 45. Struttura del G 1-64 bis N clorobenzil tropanium 3 alfa gamma glutarato dibromuro :bistropinil diestere Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 46. Gyermek L, Lee C, Nguyen N. Pharmacology of G-1-64, a new non-depolarising neuromuscular blocking agent with rapid onset and short duration of action. Acta Anaesthesiol Scand 1999; 43:651-7. G-1-64 is a promising prototype of a new series of bis-quaternary ammonium salt of bistropinyl diester derivatives we have synthesized and studied in the laboratory. METHODS: Neuromuscular block (NMB) and autonomic and cardiovascular side effects were studied on appropriate preparations of anesthetized rats, rabbits, cats, ferrets, pigs and monkeys. Neuromuscular blocking characteristics, cumulativeness, and pharmacological reversibility were determined. Cardiac vagal block was evaluated by the inhibition of the bradycardic response to stimulation of the vagus in the cat, rat, ferret, and pig. Sympathetic ganglion block was evaluated on the cat's superior cervical ganglion/nictitating membrane preparation. Arterial blood pressure and heart rate were determined in all species. RESULTS: G-1-64 produced nondepolarizing NMB with train-of-four (TOF) and tetanic fades, and reversible with anticholinesterases. Its ED50 ranged between 60 and 800 microg/kg in these species. It showed a significantly faster onset (0.9-2.1 min) and/or shorter duration of action (512 min) than either atracurium or mivacurium. It did not show cumulativeness on repeated doses or infusion. A varying degree of cardiac vagal block was present, dependent on the species at doses exceeding the ED80 for NMB. Cardiovascular changes, ganglion block or signs suggesting histamine release were absent. CONCLUSION: With favorable neuromuscular blocking characteristics and modest side effects, G-1-64 and similar derivatives may have clinical potential. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 47. Pharmacology This is a bis-quaternary ammonium salt of a bistropinyl diester derivative. The molecule was selected from more than 200 tropinyl diester compounds. These agents are characterized by: 1. A connecting chain of acid diesters attached to the C3 atom of two tropine molecules. 2. Bulky quaternary substitutes on the tropine N atoms. 3. Varying interonium distances between the terminal groups. G-1-64 is the prototype of this series of compounds, with an interonium distance of 14.74 Å. It is not yet known how this compound is metabolized. Such diesters could be predicted to undergo hydrolysis in the plasma. Another tropinyl diester compound, N-(3,4-diacetoxybenzyl)-tropinium-3a-yl] glutarate dibromide (TAAC3), has also undergone investigation in animals and appears to undergo non-organ dependent elimination. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 48. Gyermek L, Lee C, Cho YM, Nguyen N, Tsai SK. Neuromuscular pharmacology of TAAC3, a new nondepolarizing muscle relaxant with rapid onset and ultrashort duration of action. Anesth Analg. 2002 Apr;94(4):879-85, We selected bis [N-(3,4-diacetoxybenzyl) tropanium-3a-yl] glutarate dibromide (TAAC3) from many new tropinyl diester derivatives to evaluate its neuromuscular blocking (NMB) and autonomic side effects on anesthetized rats, rabbits, guinea pigs, cats, pigs, dogs, and monkeys. NMB potency, onset, recovery index, and duration of action were determined. Comparisons of these pharmacologic variables were made between TAAC3 and rocuronium. In the cat, the degrees of train-of-four and tetanic fade, posttetanic potentiation, and pharmacologic antagonism were evaluated. For determination of the NMB maintenance dose, TAAC3 was also given to rabbits and pigs in the initial dose/maintenance infusion mode. Cardiac vagal block was evaluated in the rat, pig, cat, and guinea pig on the basis of the inhibition of the bradycardia to stimulation of the vagus nerve. Sympathetic ganglion block was studied on the superior cervical ganglion-nictitating membrane preparation of the cat. TAAC3 produced nondepolarizing NMB. Its NMB 90% effective doses ranged from 90 to 425 mg/kg, depending on the species. TAAC3 had a faster onset (0.8–1.0 min), shorter recovery index (0.6–1.1 min), and shorter duration of action (1.8–3.5 min) than rocuronium. It produced a slight cumulative effect on infusion, but not on repeated single-dose administration. Cardiac vagal block was present at doses exceeding the NMB 90% effective dose. In the cat and pig at equipotent NMB doses, the degree of cardiac vagal block was similar to that of rocuronium. There was no demonstrable sympathetic ganglion block in the cat. In view of its favorable NMB characteristics, TAAC3 is now undergoing detailed preclinical studies. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 49. bis [N-(3,4-diacetoxybenzyl) tropanium-3a-yl] glutarate dibromide (TAAC3) : BISTROPINIL DIESTERE Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 50. bis [N-(3,4-diacetoxybenzyl) tropanium3a-yl] glutarate dibromide (TAAC3) Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 51. bis [N-(3,4-diacetoxybenzyl) tropanium3a-yl] glutarate dibromide (TAAC3) Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 52. Durate comparative (min) TAAC3,Rocuronium,rapacuronium nel maiale 7 6 5 min 4 TAAC3 ROCU RAPA 3 2 1 0 ED95 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) Infus 1 hr
  • 53. SZ 1677 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 54. E. S. VIZI , Z. TUBA S. MAHO , F. F. FOLDES , 0. NAGANO , M. D0DA , S. TAKAG, , A. CHAUDHRy , A. J. SAUBERMANN , H. NAGASHIMA A new short‑ acting non‑ depolarizing muscle relaxant (SZ1677) without cardiovascular side‑ effects.Acta Anesth Scand 2003;47:291-300 Background: In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non‑depolarizing muscle relaxant without cardiovascular side ‑effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non ‑depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, IV13) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants. Methods: Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i) in vitro isolated phrenic nerve‑hemidiaphragm preparation of mice, rats and guinea pigs and (ii) in vivo sciatic nerve‑anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine‑induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence. Results: One of more than 120 newly synthesized non ‑depolarizing muscle relaxants compounds, 1 ‑3[C~- hydroxy‑ 17P‑ acetyloxy‑ 2f'‑ (1,4‑ dioxa‑ 8‑ azaspiro[4,5]dec‑ 8‑ yl)‑ 50~‑ androstane‑ l6P‑ ilI ‑ 1‑ (2propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side ‑effects. Pharmacodynamic studies show that SZ1 677 is a non‑depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED9o. This compound, unlike many other muscle relaxants, does not have atropine ‑like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1 677 compares favorably with all presently available short ‑acting muscle relaxants, including rapacuronium. Conclusion: In experiments, SZ1677 proved to be a short ‑acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side ‑effects. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 55. Struttura chimica dell’SZ 1677 e del suo principale metabolita Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 56. SZ 1677:farmacodinamica((VIZI et al .A new short‑ acting non‑ depolarizing muscle relaxant (SZ1677) without cardiovascular side‑ effects.Acta Anesth Scand 2003;47:291-300) Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 57. SZ 1677:Effetto sulla trasmissione nm.nel preparato nervo frenico- emidiaframma di cavia.(VIZI et al .A new short‑ acting non‑ depolarizing muscle relaxant (SZ1677) without cardiovascular side‑ effects.Acta Anesth Scand 2003;47:291-300) Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 58. SZ 1677;farmacodinamica e antagonizzazione (VIZI et al .A new short‑ acting non‑ depolarizing muscle relaxant (SZ1677) without cardiovascular side‑ effects.Acta Anesth Scand 2003;47:291-300 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 59. Effetti temporali dei vari miorilassanti(ED 90) negli animali da esperimento. (VIZI et al .A new short‑ acting non‑ depolarizing muscle relaxant (SZ1677) without cardiovascular side‑ effects.Acta Anesth Scand 2003;47:291-300) SZ 1677:ratto 120,0 SZ 1677:cavia SZ1823 100,0 panc 80,0 vecu pipec 60,0 rocu ratto rocu cavia 40,0 rapac ratto rapac cavia 20,0 0,0 onset T1 25% T1 75% Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) T1 bas RR 25-75%
  • 60. author species drug Belmont Animals humans GW280430 <2 min A 6-9 Gyermek animals TAAC 3 <2min 5-10 Vizi animals Sz1677 <2 min <12 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) onset Duration (min)
  • 61. Adverse effects HeerdtHeerdt PM, Hashim MA, Wastilla W, Mook RA, Savarese JJ. Cardiopulmonary effects of the ultrashort neuromuscular blocking drug GW280430A in dogs. Anesthesiology 1999; 91:A1024. has studied the effect of GW280430A on the respiratory system of six male beagles; he measured pulmonary artery pressures, peak inspiratory pressure and pulmonary compliance. He found no change in these variables at doses up to 25xED95 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 62. Cardiac effects of TAAC 3 Studies of the cardiovascular properties of the tropinyl diesters have considered only the degree of vagal block produced. This is evaluated by studying the inhibition of the bradycardic response to peripheral stimulation of the cut right vagus nerve with 15–20 Hz supramaximal impulses delivered every 2 min. Gyermek found that all the tropinyl diesters studied produced vagal block in the rat. The least potent compounds (which have the slowest onset of action and longest duration of effect), produced 70–90% vagal block, whereas the more potent tropinyl diesters (the most rapid onset of action and the most rapid offset) produced only 40% vagal block. Investigation of TAAC3 in anaesthetized cats also suggests that this tropinyl ester has the potential to produce changes in heart rate and arterial pressure. The fact that as potency increases, the side-effect profile of these drugs becomes more favourable is encouraging, as it is these more potent agents which promise to be of most clinical benefit. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 63. Cardiovascular side-effects of GW280430A The cardiovascular side-effects of GW280430A have been investigated in dogs, cats, and human volunteers. Heerdt measured heart rate, systemic and pulmonary artery pressures, left ventricular pressure, end-diastolic pressure, and cardiac index in beagles given increasing doses of GW280430A. Other than a transient decrease in arterial pressure at 25xED95, GW280430A did not alter any of the variables. When Belmont examined the effect of GW280430A on the cardiovascular system of cats by measuring heart rate, arterial pressure and per cent vagal inhibition, he was able to give 10xED95 before producing a transient but significant decrease in arterial pressure and a rise in heart rate. Forty per cent vagal block was produced at 16xED95. Lein has reported the effects of GW280430A in 16 male volunteers using doses up to 3xED95 and measuring maximal heart rate and arterial pressure changes in the 5 min following administration. She found that no volunteer had a maximal change in heart rate or arterial pressure of greater than 10% from baseline. Belmont MR, Apperley G, Hashim MA, Patel S, Savarese JJ. The neuromuscular and cardiovascular profile of GW280430A, a new ultrashort-acting muscle relaxant in cats. Anesthesiology 1999; 91:A 1025. 54: Heerdt PM, Hashim MA, Wastilla W, Mook RA, Savarese JJ. Cardiopulmonary effects of the ultrashort neuromuscular blocking drug GW280430A in dogs. Anesthesiology 1999; 91:A1024. 55: Heerdt PM, Hashim MA, Wastilla W, Mook RA, Savarese JJ. Pharmacodynamics of the novel neuromuscular blocking drug GW280430A in dogs. Anesthesiology 1999; 91:A1023. 78: Lien CA, Belmont MR, Tjan J, Fisher GR, Savarese JJ. Determination of the cardiovascular effects of GW280430A in anesthetized male volunteers. Anesthesiology 1999; 91:A1015. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 64. I nuovi antagonisti decurarizzanti Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 65. New reversal agents:i nuovi antagonisti AChE hanno effetti cardiovascolari ed intestinali indesiderati Concetto della chelazione chimica Cyclodextrins are a group of cyclic oligosaccharides, which are recognized to encapsulate lipophilic molecules including steroids. Org 25969 has been investigated in monkeys and been found to antagonize residual block produced by rocuronium more rapidly than neostigmine, without any significant cardiovascular changes. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 66. 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. Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 67. Referenze in Pubmed.(sept 2003) Epemolu O, Mayer I, Hope F, Scullion P, Desmond P. Liquid chromatography/mass spectrometric bioanalysis of a modified gamma-cyclodextrin (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 Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structureactivity relationships. J Med Chem. 2002 Apr 25;45(9):1806-16. Tarver GJ, Grove SJ, Buchanan K, Bom A, Cooke A, Rutherford SJ, Zhan 2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker rocuronium bromide. di Faenza(RA) Servizio di Anestesia e Rianimazione Ospedale
  • 68. ORG 25969 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 69. Rocuronium incapsulato nella gammaciclodestrina Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 70. 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 Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 71. Bom et al.Rapid reversal of rocuronium inducd neuromuscular block by ORG 25969 is independent of renal perfusion.Anesthesiology 2003;A1158 BOM Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 72. Epemolu 0, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. The purpose of this study was to determine the changes in the plasma concentration of rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block‑reversal agent, in anesthetized guinea pigs. METHODS: Rocuronium was infused for I h at a rate of 12‑19 nmol.kg‑l.min‑I to produce a steady‑state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol.kg‑l.min‑I or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography‑mass spectrometry/mass spectrometry. RESULTS: In both treatment groups, a steady‑state plasma concentration of rocuronium was obtained after 30 min. In the saline‑treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline‑treated group, a small increase in the postmortem bladder concentration of rocuronium was detected. CONCLUSIONS: The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).sz Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 73. 1)White PF rapacuronium:why did it fail as a replacement for succinylcholine? Br.J.Anaesth.2002;88;163-65. 2) Baillard C, Gehan G, Reboul‑Marty J, etal. Residual curarization in the recovery room after vecuronium. Br J Anaesth 2000; 84:394‑395. 3) Hayes AH, Mirakhur RK, Breslin DS, et al. Postoperative residual block after intermediate‑acting neuromuscular blocking drugs. Anaesthesia 2001; 56:312‑318. 6)Palin R, Clark JK, Cowley P, Muir AW, Pow E, Prosser AB, Taylor R, Zhang MQ. Novel piperidinium and pyridinium agents as watersoluble acetylcholinesterase inhibitors for the Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 74. Pharmacodynamics of GW280430A:AP data Pharmacodynamics of GW280430A:AP data Belmont et al.BJA 1999 Belmont et al.BJA 1999 14,6 15,2 11,9 12,5 16 14 12 10 8 6 4 2 0 12,2 9,8 9,3 9,5 9,9 7 1,5 7,4 Legend 0,18 mg/kg 0,36 mg/kg 0,54 mg/kg 95% rec 4,7 1,7 16 14 12 10 8 6 4 2 0 75% rec 2,6 25% rec onset New New Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 75. Pharmacodynamics of GW 280430A:larynx BElmont et al BJA 1999 BElmont et al BJA 1999 15 16,1 18 16 14 12 10 8 6 4 2 0 12,7 12,9 9,3 11,2 11,3 9,6 7,2 9,4 7,7 0,9 5,6 1,1 18 16 14 12 10 8 6 4 2 0 95% rec 75% rec 1,6 25% rec onset Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)