Residual paralysis

1. Come Evitare la paralisi residua e vivere felici :il sugammadex . C.Melloni Libero professionista Napoli SIA 2013

2. Residual neuromuscular block Napoli SIA 2013

3. Italian survey 2010 ( Minerva Anestesiol . 2012 Jul;78(7):767-73. Neuromuscular block in Italy : a survey of current management. Della Rocca G, Iannuccelli F, Pompei L, Pietropaoli P, Reale C, Di Marco P Acta Anaesthesiol Scand. 2010 Mar;54(3):307-12. doi : 10.1111/j.1399-6576.2009.02131.x. Epub 2009 Oct 15. Knowledge of residual curarization : an Italian survey. Di Marco P, Della Rocca G, Iannuccelli F, Pompei L, Reale C, Pietropaoli P. Napoli SIA 2013 Only 35% of italian anesthesiologists use TOF......... 73% of italian anesthesiologists rely on clinical signs for return of muscular power 24% know that before extubation at least a TOF 0f 0.90 is needed

4. Napoli SIA 2013

5. What is adequate neuromuscular recovery ? Ability to breathe normally;TV,paO2,SaO2,etCO2,PEF,FEV.... maintain a patent upper airway , preserve protective airway reflexes , swallow , cough , smile , Talk. Arm and leg movements ....... . Napoli SIA 2013

6. TOF( R ) introduced in the early 1970s by Ali et al . Four supramaximal stimuli are delivered every 0.5 second (2 Hz ) muscle response to the fourth stimulus is compared with that of the first stimulus . Fade of force of muscle contraction in response to repetitive nerve stimulation provides the basis for evaluation ; the degree of fade is proportional to the intensity of the neuromuscular block . Advantages : does not require a control ,prerelaxant twitch height less pain on stimulation over tetanic stimulation lack of posttetanic facilitation Threshold ?????? Napoli SIA 2013

7. TOFR=D/A Napoli SIA 2013

8. Napoli SIA 2013

9. Napoli SIA 2013 Innervator Fisher & Paykel e TOfWatch Organon

10. TOFR thresholds (in the definition of residual neuromuscular block ) 1970 –1977 a mean TOF ratio of 0.74 represented“ acceptable recovery ” from d-tubocurarine blockade . Patients with this level of recovery were able to open eyes widely , cough , protrude the tongue , sustain head lift for 5 seconds , develop a forced vital capacity of at least 15 to 20 mL /kg, and sustain tetanic stimulation without fade for 5 seconds . , changes in measured respiratory variables , including tidal volume , vital capacity , inspiratory force , and peak expiratory flow rate, were “ negligible ” until TOF ratios decreased To 0.6. At a TOF ratio of 0.7 , all patients were able to sustain eye opening , hand grasp , and tongue protrusion , whereas 9 of 10 were able to maintain a 5-second head li ft Ali HH, Kitz RJ. Evaluation of recovery from nondepolarizing neuromuscular block , using a digital neuromuscular transmission analyzer : preliminary report. Anesth Analg 1973;52:740–5. AliHH,Wilson RS, Savarese JJ, Kitz RJ. The effect of tubocurarineon indirectly elicited train -of- four muscle response and respiratory measurements in humans . Br J Anaesth 1975;47:570–4 Brand JB, Cullen DJ, Wilson NE, Ali HH. Spontaneous recovery from nondepolarizing neuromuscular blockade : correlation between clinical and evoked responses . Anesth Analg 1977;56:55–8. Napoli SIA 2013

11. Napoli SIA 2013

12. Train of four ratio>0.7, <=0.9 1997-2000 TOFR 0.9 to ensure optimal patient safety . pharyngeal dysfunction and an increased risk for aspiration occur at TOF ratios 0.9. Impaired inspiratory flow and partial upper airway obstruction have been observed frequently at TOF ratios of 0.8 . subtle levels of neuromuscular blockade may produce distressing symptoms in awake patients , which may persist even at TOF ratios 0.9. These recent data suggest that the new “ gold standard” for the minimal acceptable level of neuromuscular recovery is an EMG or MMG TOF ratio of 0.9 (or perhaps 1.0 when AMG is used Napoli SIA 2013

13. Post Operative Residual curarization PORC Napoli SIA 2013

14. Postoperative residual paralysis PORP Napoli SIA 2013

15. Postoperative residual neUromuscular blockade or weakness PO RE NMB ?? Napoli SIA 2013

16. Dichiarazione di assenza di conflitto di interessi non ho alcun interesse finanziario o attività commerciale né sono supportato dalla azienda produttrice del Sugammadex ( Bridion ). Napoli SIA 2013

17. 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 . Napoli SIA 2013 Dtc Galla panc var i Atrac panc Atrac galla Panc vecu Panc vecu panc panc panc Tof <70 Tof <90

18. PORC % nella metanalisi di Naguib ;parte II Napoli SIA 2013

19. Residual Paralysis at the Time of Tracheal Extubation Glenn S. Murphy, Joseph W . Szokol , Jesse H. Marymont , Mark Franklin, Michael J . Avram, Jeffery S. Vender. ( Anesth Analg 2005;100:1840–5) Napoli SIA 2013 Midazolam,1 –2 mg .; propofol 1.5– 2.5 mg/kg , fentanyl , sevoflurane 0.5%–3.5% in an air/ oxygen mixture . neuromuscular blockade was reversed with neostigmine 50 microg /kg and glycopyrrolate 10 micro g/ kg adequacy of neuromuscular reversal using standard clinical criteria :( 5-s head lift or hand grip , eye opening on command , negative inspiratory force more than 20 cm H2 O, or vital capacity breath 15 cc/kg) and peripheral nerve stimulation (no evidence of fade with TOF or tetanic stimulation [50 Hz]). A 5-s head lift (or hand grip ) and the observation of an absence of fade with peripheral nerve stimulation were the minimal requirements Nm block maintained at TOF 1-2 12% only with tof >0.9 120 pts

20. Residual Paralysis at the Time of Tracheal Extubation Glenn S. Murphy, Joseph W . Szokol , Jesse H. Marymont , Mark Franklin, Michael J . Avram, Jeffery S. Vender. ( Anesth Analg 2005;100:1840–5) The use of a peripheral nerve stimulator in the OR may reduce, but does not eliminate, the problem of postoperative paresis . Detection of incomplete reversal of neuromuscular blockade is difficult with standard TOF or tetanic stimulation . Experienced observers are unable to detect fade when the TOF ratio is 0.4 Viby -Mogensen J , Jensen NH, Englbaek J , et al. Tactile and visual evaluation of the response to train -of- four nerve stimulation . Anesthesiology 1985;63:440 –3. ) . Napoli SIA 2013

21. Residual Neuromuscular Block : Lessons Unlearned . Part I: Definitions , Incidence , and Adverse Physiologic Effects of Residual Neuromuscular Block Glenn S. Murphy , Sorin J . Brull , Anesth Analg 2010;111:120– 8 Napoli SIA 2013

22. What are the factors that alter the incidence of postoperative residual paralysis ? The great variability is due to different methods : use of T4/T1 ratio of 0.7, 0.8 or 0.9 as PORP criterion use of different NMB of short, intermediate and long- term duration use of single or repeated doses , or continuous infusion of NMB assessment method of the residual NMB with or without reversal of neuromuscular blockade at the end of anesthesia with anticholinesterase drugs with dose and interval between the anticholinesterase drugs and degree assessment of neuromuscular blockade Age presence of kidney , cardiac or neuromuscular dysfunction drug use that can alter the pharmacodynamics and/or pharmacokinetics of NMB ( calcium channel blockers , magnesium , lithium , antibiotics , local anesthetics , inhaled anesthetics , opioids , benzodiazepines electrolyte abnormalities , metabolic or respiratory acidosis and hypothermia . Napoli SIA 2013

23. Napoli SIA 2013

24. 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 Napoli SIA 2013

25. Napoli SIA 2013 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

26. Napoli SIA 2013 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??

27. Napoli SIA 2013 Assiomi della ripresa nm. TOF > 0.70 sicuro indice della ripresa nm ……….. Ali HH, Wilson RS, Savarese JJ, Kitz RJ: The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth 47:570-4, 1975 Brand JB, Cullen DJ, Wilson NE, Ali HH: Spontaneous recovery from nondepolarizing neuromuscular blockade: Correlation between clinical and evoked responses. Anesth Analg 56:55-8, 1977

28. Napoli SIA 2013 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

29. Napoli SIA 2013 Rivalutazione della pratica clinica Età e stato di salute differiscono fra volontari sani e pazienti! La prassi clinica e l’utilizzo dei miorilassanti variano fra i diversi centri ambulatoriali il monitoraggio degli effetti nm non è praticato in ospedale,figurarsi nei centri ambulatoriali! I metodi di monitoraggio usati da Kopman et al si applicano ad una ampia gamma di situazioni cliniche. Esistono pesanti pressioni economiche per la diminuzione della spesa sanitaria.

30. Napoli SIA 2013 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 .

31. Napoli SIA 2013 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 )?

32. Napoli SIA 2013

33. 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 Napoli SIA 2013

34. Chemorec.perif Chemrecett.centr SNC Ipossia ipercapnia iperventilazione Napoli SIA 2013

35. Corpi carotidei Sito nicotinico Sito muscarinico nmb atropina ipossia Napoli SIA 2013

36. Eriksson LI,Sundman E,Olsson R,NilssonL,Witt H,Ekberg O,Kuylenswtierna R. Functional Assessment of the Pharynx at Rest and during Swallowing in Partially Paralyzed Humans: Simultaneous Videomanometry and Mechanomyography of Awake Human Volunteers, Anesthesiology 1997;67:1035-43. Napoli SIA 2013

37. Napoli SIA 2013

38. Eriksson LI,Sundman E,Olsson R,NilssonL,Witt H,Ekberg O,Kuylenswtierna R. Functional Assessment of the Pharynx at Rest and during Swallowing in Partially Paralyzed Humans: Simultaneous Videomanometry and Mechanomyography of Awake Human Volunteers,Anesthesiology 1997;67:1035-43 . Vecuronium induced partial paralysis(tof o.60-0.80) cause pharyngeal disfunction: upper esophageal sphincter tone Pharynx muscle coordination Bolus transit time 6/14 volunteers aspirated at tof<0.90 Napoli SIA 2013

39. Napoli SIA 2013

40. The Incidence and Mechanisms of pharyngeal and Upper Esophageal Dysfunction in Partially Paralyzed humans .Eva Sundrnan,H anne Witt, Rolf Olsson, Olle Ekberg , S Richard Kuylenstierna , Lars I. Eriksson.Anesthesiology 2000;92:977-84 20 healthy volunteers studied awake during liquid-contrast bolus swallowing. The incidence of pharyngeal dysfunction was studied by fluoroscopy .+ Simultaneous manometry After control recordings, an iv infusion of atracurium was administered to obtain TOF 0.60 , 0.70, and 0.80, followed by recovery to a > 0.90. The incidence of pharyngeal dysfunction increased to 28 %, 17 %, and 20% at TOF 0.60 , 0.70, and 0.80, respectively. Pharyngeal dysfunction occurred in 74/ 444 swallows, the majority ( 80%) resulting in laryngeal penetration. The initiation of the swallowing reflex was impaired during partial paralysis The pharyngeal coordination was impaired at train-of-four ratios of 0.60 and 0.70 . A marked reduction in the upper esophageal sphincter resting tone was found, as well as a reduced contraction force in the pharyngeal constrictor muscles. The bolus transit time did not change significantly. . Napoli SIA 2013

41. Time interval between passage of bolus from the anterior faucial arches and hyoid bone ms

42. Time interval between start of contraction of pharyngeal constrictor and start of relaxation of upper esophageal sphincter ms

43. Resting tension of the upper esophageal sphincter

44. Pharyngeal constrictor muscle function Napoli SIA 2013

45. The Incidence and Mechanisms of pharyngeal and Upper Esophageal Dysfunction in Partially Paralyzed humans Partial neuromuscular paralysis caused by atracurium is associated with a four- to fivefold increase in the incidence of misdirected swallowing. The mechanism behind the pharyngeal dysfunction is 1) a delayed initiation of the swallowing reflex, 2)impaired pharyngeal muscle function , 3)impaired coordination . The majority of misdirected swallows resulted in penetration of bolus to the larynx Napoli SIA 2013

46. Residual neuromuscular block affects pulMonary function Napoli SIA 2013

47. Acta Anaesthesiol Scand. 2004 Mar;48(3):365-70. Predictive value of mechanomyography and accelerometry for pulmonary function in partially paralyzed volunteers. Eikermann M, Groeben H, Hüsing J, Peters J. : In awake partially paralyzed volunteers spirometrically assessed pulmonary function every 5 min until recovery . Rocuronium (0.01 mg kg(-1) + 2-10 microg kg(-1) min(-1)) was administered to maintain train-of-four (TOF)-ratios (assessed every 15 s) of approximately 0.5 and 0.8 over a period of more than 5 min. The TOF-ratio associated with 'acceptable' pulmonary recovery [ forced vital capacity (FVC) and forced inspiratory volume in 1 s (FIV1) of > or =90% of baseline] was calculated using a linear regression model. During 5-min periods of repetitive nerve stimulation we compared the squared residuals of the FVC and FIV1 estimates from TOFACM vs. TOFMMG, and compared variance of values derived from ACM and MMG using Wilcoxon's test. RESULTS: TOF ACM(0.56 (0.22-0.71) [mean (95%CI) and 0.6 MMG ( 0.28-0.74)] , respectively, predict 'acceptable' (90%) recovery of FVC while FIV1 remains impaired until TOF-ratios of 0.91 (0.82-1.07) and 0.95 (0.82-1.18), respectively. Napoli SIA 2013

48. Anesthesiology. 2012 Dec;117(6):1234-44.. Residual neuromuscular blockade affects postoperative pulmonary function. Kumar GV, Nair AP, Murthy HS, Jalaja KR, Ramachandra K, Parameshwara G. Napoli SIA 2013

49. Heier T,. Caldwell,JE . Feiner JR, Liu , L, Ward , T, B,. Wright PMC. Relationship between Normalized Adductor PollicisTrain -of- four Ratio and Manifestations of Residual Neuromuscular Block A Study Using Acceleromyography during Near Steady– stateConcentrations of Mivacurium Anesthesiology 2010 : 113 ;2010 .825-832 . 12 healthy volunteers 3 steady –state levels of neuromuscular block were achieved with mivacurium infusions . TOF ratio of 0.85– 0.95 (block level 1), TOF ratio of 0.65– 0.75 ( block level 2), and TOF ratio of 0.45– 0.55 (block level 3). TOF ratio was measured acceleromyographically at the adductor pollicis using a preload . Lung volume measurements and a series of clinical tests were made at each stable block and reconciled to the normalized TOF measures . Results : None experienced airway obstruction or arterial oxygen desaturation , even at normalized TOF ratio less than 0.4 . Functional residual capacity remained unchanged whereas vital capacity decreased linearly with decreasing TOF ratio. The ability to protrude the tongue was preserved at all times . The ability to clench the teeth was lost in one volunteer at normalized TOF ratio of 0.84 but retained in four at normalized TOF ratio less than 0.4. Four volunteers lost the ability both to raise the head more than 5 s and to swallow , with the most sensitive individual demonstrating these effects at normalized TOF ratio of 0.60. At mean normalized TOF ratio of 0.42, the mean handgrip strength was approximately 20% of baseline value . Conclusion : Lung vital capacity decreased linearly with decreasing TOF ratio. Responses to clinical tests of muscle function varied to a large extent among individuals at comparable TOF ratios . None of the volunteers had significant clinical effects of neuromuscular block at normalized acceleromyographic TOF ratio greater than 0.90. Napoli SIA 2013

50. The relationship between normalized acceleromyography adductor pollicis train -of- four (AMG AP TOF) ratio and vital capacity of the lungs and between normalized AMG AP TOF ratio and handgrip strength in 12 volunteers during stable mivacurium blocks.Both vital capacity and handgrip strength decreased significantly with decreasing AMG AP TOF ratio. Heier T,. Caldwell,JE . Feiner JR, Liu , L, Ward , T, B,. Wright PMC. Relationship between Normalized Adductor PollicisTrain -of- four Ratio and Manifestations of Residual Neuromuscular Block A Study Using Acceleromyography during Near Steady– stateConcentrations of Mivacurium Anesthesiology 2010 : 113 ;2010.825-83 Napoli SIA 2013

51. Number of individuals who lost muscle functions TOF ratio of 0.85– 0.95 (block level 1), TOF ratio of 0.65– 0.75 (block level 2), and TOF ratio of 0.45– 0.55 (block level 3). TOFR 0.85-0.95 TOFR 0.65-0.75 TOFR ratio of 0.45 –0.55 Napoli SIA 2013

52. Anesthesiology. 2003 Jun;98(6):1333-7. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Eikermann M, Groeben H, Hüsing J, Peters J. Source Klinik für Anästhesiologie und Intensivmedizin , Universitätsklinikum Essen, Germany. [email protected] Abstract BACKGROUND: Residual paralysis increases the risk of pulmonary complications but is difficult to detect. To test the hypothesis that accelerometry predicts effects of residual paralysis on pulmonary and upper airway function, the authors related tests of pulmonary and pharyngeal function to accelerometry of adductor pollicis muscle in 12 partially paralyzed volunteers. METHODS: Rocuronium (0.01 mg/kg + 2-10 microg x kg-1 x min-1) was administered to maintain train-of-four (TOF) ratios (assessed every 15 s) of approximately 0.5 and 0.8 over a period of more than 5 min. The authors evaluated pharyngeal and facial muscle functions during steady state relaxation and performed spirometric measurements every 5 min until recovery. Upper airway obstruction was defined as a mean ratio of expiratory and inspiratory flow at 50% of vital capacity of greater than 1. The TOF ratio associated with "acceptable" pulmonary recovery (forced vital capacity and forced inspiratory volume in 1 s of > or =90% of baseline) was calculated using a linear regression model. RESULTS: At peak blockade (TOF ratio 0.5 +/- 0.16), forced inspiratory flow was impaired (53 +/- 19%) to a greater degree than forced expiratory flow (75 +/- 20%) with a mean ratio of expiratory and inspiratory flow at 50% of vital capacity of 1.18 +/- 0.6. Upper airway obstruction, observed in 8 of 12 volunteers, paralleled an impaired ability to swallow reported by 10 of 12 volunteers. In contrast, all volunteers except one could sustain a head lift for more than 5 s. The authors calculated that a mean TOF ratio of 0.56 (95% confidence interval, 0.22-0.71) predicts "acceptable" recovery of forced vital capacity, whereas forced inspiratory volume in 1 s was impaired until a TOF ratio of 0.95 (0.82-1.18) was reached. A 100% recovery of TOF ratio predicts an acceptable recovery of forced vital capacity, forced inspiratory volume in 1 s, and mean ratio of expiratory and inspiratory flow at 50% of vital capacity in 93%, 73%, and 88% of measurements (calculated negative predictive values), respectively. CONCLUSION: Impaired inspiratory flow and upper airway obstruction frequently occur during minimal neuromuscular blockade (TOF ratio 0.8), and extubation may put the patient at risk. Although a TOF ratio of unity predicts a high probability of adequate recovery from neuromuscular blockade, respiratory function can still be impaired. Comment in Residual neuromuscular blockade: importance of upper airway integrity. [Anesthesiology. 2004 Napoli SIA 2013

53. Anesthesiology. 2003 Jun;98(6):1333-7. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Eikermann M, Groeben H, Hüsing J, Peters J. Napoli SIA 2013

54. Muscle function and tofr in 12 partially paralyzed volunteers Anesthesiology . 2003 Jun;98(6):1333-7. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Eikermann M, Groeben H, Hüsing J, Peters J. Napoli SIA 2013

55. Eikermann 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 partialneuromuscular blockade . Am J Respir Crit Care Med 2007;175:9–15 Partial neuromuscular blockade ( train -of- four [TOF] ratio: 0.5 and 0.8) was associated with the following : (1) a decrease of inspiratory retropalatal and retroglossal upper airway volume to 66 ( 22) and 82 (12)% of baseline, whichwas significantly more intense in the retropalatal area; ( 2) an attenuation of the normal increase in anteroposterior upper airway diameter during forced inspiration to 74 (18)% of baseline; ( 3) a decrease in genioglossus activity during maximum voluntary tongue protrusion to 39 (19)% (TOF, 0.5) and 73 (29)% (TOF, 0.8) of Baseline ( 4) no effects on upper airway size during expiration , lung volume, and respiratory timing. Conclusions: Thus, impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function. This may be explained by an impairment of the balance between upper airway dilating forces and negative intraluminal pressure generated during inspiration by respiratory “pump” muscles . Napoli SIA 2013

56. T1-weighted spin echo magnetic resonance midsagittal image of a subject before neuromuscular blockade ( baseline Napoli SIA 2013

57. End- inspiratory and end- expiratory upper airway volume before neuromuscular blockade (baseline) at a steady-state train -of- four ( TOF) ratio of 0.5 and 0.8, after recovery of the TOF ratio to 1.0, and15 min later ( same TOF ratio) . Before neuromuscular blockade and with recovery from neuromuscular blockade , end- inspiratory volume was significantly greater than end- expiratory volume . End- inspiratory volume decreased significantly during partial neuromuscular blockade , and was even lower than end- expiratory upper airway volume at a TOF ratio of 0.5. Napoli SIA 2013

58. Upper airway volume at end inspiration ( quiet breathing ) before neuromuscular blockade , at a steady-state TOF ratio of 0.5 and 0.8 , after recovery of the TOF ratio to 1.0, and 15 min later . Upperpanel : retroglossal area; lower panel: retropalatal area . 15 min. During partial neuromuscular blockade , upper airway volume decreased significantly both in the retroglossal and retropalatal part of the upper airway , but was no longer significantly different from baseline values with recovery of the TOF ratio to 1.0. However , 4 of 10 volunteers still showed a marked impairment of retropalatal airway volume despite recovery of the TOF ratio to unity , which disappeared within 15 min. Napoli SIA 2013

59. Changes in upper airway volume at end inspiration ( quiet breathing ) from baseline during steady-state neuromuscular blockade.The percentage decrease of retroglossal and retropalatal upper airway volume . At a TOF ratio of 0.5, upper airway volume decrease was significantly greater in the retropalatal area compared with the retroglossal area. Napoli SIA 2013

60. Minimum cross- sectional area at end inspiration of the retroglossal and retropalatal part of the upper airway . Measurements during quiet breathing before neuromuscular blockade (baseline) at a steadystate TOF ratio of 0.5 and 0.8, after recovery of the TOF ratio to 1.0, and 15 min later . Du ring neuromuscular blockade , airway crosssectional area decreased significantly in both regions of the upper airway and recovered to baseline values with a TOF ratio of unity . The smallest cross- sectional area of the retropalatal area was significantly less than the smallest cross- sectional area of the retroglossal area of the upper airway . Napoli SIA 2013

61. Genioglossus function Napoli SIA 2013

62. Napoli SIA 2013

63. Impaired upper airway integrity by residual neuromuscular blockade: increased airway collapsibility and blunted genioglossus muscle activity in response to negative pharyngeal pressure. Herbstreit F , Peters J , Eikermann M. Anesthesiology . 2009 Jun;110(6):1253-60 Epiglottic and nasal mask pressures , genioglossus electromyogram , respiratory timing, and changes in lung volume were measured in awake healthy volunteers ( n 15 ) before , during (TOF 0.5 and 0.8 [steady state]), and after recovery of TOF to unity from rocuronium-induced partial neuromuscular blockade . Passive upper airway closing pressure ( negative pressure drops , random order , range 2 to –30 cm H2O ) and pressure threshold for flow limitation were determined . Results : Upper airway closing pressure increased ( was less negative ) significantly from baseline by 54 (4.4)% , 37 (4.2)% , and 16 ( 4.1) % at TOF ratios of 0.5, 0.8, and 1.0.,respectively (P < 0.01 vs. baseline for any level). Phasic genioglossus activity almost quadrupled in response to negative (–20 cm H2O) pharyngeal pressure at baseline, and this increase was significantly impaired by 57 ( 44)% and 32 (6)% at TOF ratios of 0.5 and 0.8, respectively (P < 0.01 vs. baseline). End - expiratory lung volume, respiratory rate, and tidal volume did not change. Conclusion: Minimal neuromuscular blockade markedly increases upper airway closing pressure, partly by impairing the genioglossus muscle compensatory response. Increased airway collapsibility despite unaffected values for resting ventilation may predispose patients to postoperative respiratory complications , particularly during airway challenges . Napoli SIA 2013

64. . Representative recording of main variables from an awake healthy volunteer before partial neuromuscular blockade , duringimpaired neuromuscular transmission with a target train -of- four (TOF) ratio of 0.5 and 0.8 and with the TOF ratio recovered to unity .( A) Mask pressure at 2 cm H2O. Phasic ( respiratory ) genioglossus activity is very low while breathing near atmospheric pressure.Inspiratory time was longer during impaired neuromuscular transmission , but no flow limitation was observed at this maskpressure . (B) Same volunteer during a negative pressure challenge (–20 cm H2O). Before partial neuromuscular blockade , phasicgenioglossus activity is markedly increased compared to breathing near atmospheric pressure, but no flow limitation is observed ,despite such negative pharyngeal pressure. During partial neuromuscular blockade , phasic genioglossus activity is markedlyincreased compared with breathing at atmospheric pressure. However , the magnitude of the compensatory increase in genioglossus activity to negative pharyngeal pressure is impaired and flow limitation is observed . EMG electromyogram . Napoli SIA 2013

65. Upper airway closing pressure ( black bars ) significantl increased during partial neuromuscular blockade and was still abnormal , even with recovery of the TOF ratio to unity . With neuromuscular transmission intact at baseline, evidenceof flow limitation ( gray bars ) was first observed at anaverage pressure of –12 cm H2O. With partial neuromuscular blockade at a TOF ratio of 0.5 and 0.8, flow limitation occurred at significantly less negative values of mask pressure, i.e. , airway integrity is impaired Napoli SIA 2013

66. . Genioglossus activity increases markedly and significantly as negative pressure is applied . However , the magnitude of this effect is significantly attenuated with partial neuromuscular blockade Napoli SIA 2013

67. Herbstreit F , Peters J , Eikermann M. Anesthesiology . 2009;110 (6):1253-60 Minimal neuromuscular blockade (TOF ratio 0.5–1 ) markedly increased upper airway collapsibility and impaired the genioglossus response to negative pharyngeal pressure challenges . Thus , our data suggest that minimal neuromuscular blockade evokes increased upper airway collapsibility by blunting upper airway dilator compensatory responses to negative pharyngeal pressure. Imaging studies during complete or partial Eikermann 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 . Am J Respir Crit Care Med 2007; 175:9–15 neuromuscular blockade and in patients with obstructive sleep apnea suggest that the soft palate plays an important role in mediating airway narrowing during airway muscle paralysis and sleep . Napoli SIA 2013

68. 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-of-four (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 . Napoli SIA 2013

69. 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 Napoli SIA 2013

70. Bissinger U,Schimek,F,Lenz,G.Postoperative residual paralys and respiratory status:a comparative study of pancuronium and vecuronium.Physiol Rev. 2000:49;455-462. 83 patients,balanced or inhalation maintenance Panc for op>2hrs,vecu for op>1 hr PORP defined as tofr <70,hypoxemia as SaO ” > 5% lower than basal or postop SaO2<93%,hypercapnia as paCO2>46 mmHg . Napoli SIA 2013

71. Bissinger U,Schimek,F,Lenz,G.Postoperative residual paralys and respiratory status:a comparative study of pancuronium and vecuronium.Physiol Rev. 2000:49;455-462. panc vecu PORP 20% 7% hypoxemia 60% 10% hypercapnia 30% 8% Napoli SIA 2013

72. . Bissinger U,Schimek,F,Lenz,G.Postoperative residual paralys and respiratory status:a comparative study of pancuronium and vecuronium.Physiol Rev. 2000:49;455-462. Napoli SIA 2013

73. Napoli SIA 2013

74. Ma che ci importa del TOFR 0.90?

75. Paralisi residua e % di tof<0.40 in RR,subito dopo trasferimento

76. Andamento temporale del tof <0.80 nella RR

77. Postoperative pulmonary complications

78. Popc secondo il tipo di chirurgia

79. 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

80. What is the validity and correlation between the different PORP diagnostic tests ? Clinical tests have shown the following values of sensitivity , specificity , positive and negative predictive values 19 (D) : Capacity to keep the head up for 5 seconds : 0.19; 0.88; 0.51; 0.64; • Capacity to hold up the arm or the leg for 5 seconds : 0.25; 0.84; 0.50; 0.64; • Protrusion or capacity to remove the tongue : 0.22; 0.88; 0.52; 0.64; • Maintenance of hand grip strength : 0.18; 0.89; 0.51; 0.63. None of the available clinical trials showed a positive correlation with the T4/T1 > 0.9, or ruled out the possibility of PORP 7,8,19 (B) 21 (C).    

81. Br J Anaesth . 2010 Sep;105(3):304-9. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M, Schmidt U. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. Postoperative residual curarization (PORC) [train-of-four ratio (T4/T1) <0.9] is associated with increased morbidity and may delay postoperative recovery room (PACU) discharge. We tested the hypothesis that postoperative T4/T1 <0.9 increases PACU length of stay. At admission to the PACU, neuromuscular transmission was assessed by acceleromyography (stimulation current: 30 mA) in 246 consecutive patients. The potential consequences of PORC-induced increases in PACU length of stay on PACU throughput were estimated by application of a validated queuing model taking into account the rate of PACU admissions and mean length of stay in the joint system of the PACU plus patients recovering in operation theatre waiting for PACU beds. PACU length of stay was significantly longer in patients with T4/T1 <0.9 (323 min), compared with patients with adequate recovery of neuromuscular transmission (243 min). Age (P=0.021) and diagnosis of T4/T1 <0.9 (P=0.027), but not the type of neuromuscular blocking agent, were independently associated with PACU length of stay. The incidence of T4/T1 <0.9 was higher in patients receiving vecuronium . Delayed discharge significantly increases the chances of patients having to wait to enter the PACU. The presence of PORC is estimated to be associated with significant delays in recovery room admission. CONCLUSIONS: PORC is associated with a delayed PACU discharge. The magnitude of the effect is clinically significant. In our system, PORC increases the chances of patients having to wait to enter the PACU . Napoli SIA 2013

82. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Napoli SIA 2013

83. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Napoli SIA 2013

84. DO we always need to reverse nmb ? Napoli SIA 2013

85. Anesthesiology. 2005 Feb;102(2):257- 68 . Impact of anesthesia management characteristics on severe morbidity and mortality. Arbous MS, Meursing AE, van Kleef JW, de Lange JJ, Spoormans HH, Touw P, Werner FM, Grobbee DE. A case-control study was performed of all patients undergoing anesthesia (1995-1997 ): 869,483 patients; 807 cases and 883 controls were analyzed ONLY coma or death reported during or within 24 h of undergoing anesthesia .. .The incidence of 24-h postoperative death was 8.8 ( 8.2-9.5) per 10,000 anesthetics. The incidence of coma was 0.5 (0.3 -0.6) . Anesthesia management factors that associated with a decreased risk : equipment check with protocol and checklist, documentation of the equipment check , a directly available anesthesiologist, no change of anesthesiologist during anesthesia, presence of a full-time working anesthetic nurse two persons present at emergence, reversal of anesthesia (for muscle relaxants and the combination of muscle relaxants and opiates ; postoperative pain medication as opposed to no pain medication , particularly if administered epid or i.m . as opposed toi.v . . Napoli SIA 2013

86. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Herbstreit F , Zigrahn D, Ochterbeck C, Peters J , Eikermann M. Anesthesiology . 2010 ;113 (6):1280-8. 10 healthy male volunteers epiglottic and nasal mask pressures , genioglossus electromyogram , air flow, respiratory timing, and changes in lung volume before , during (TOF ratio: 0.5), and after recovery of the TOF ratio to unity , and after administration of neostigmine 0.03 mg/kg IV (with glycopyrrolate 0.0075 mg/kg). Upper airway critical closing pressure ( Pcrit ) was calculated from flow- limited breaths during random pharyngeal negative pressure challenges . Pcrit increased significantly after administration of neostigmine / glycopyrrolate compared with both TOF recovery ( mean SD, by 27 21%; P 0.02) and baseline (by 38 17 %; P 0.002). In parallel, phasic genioglossus activity evoked by negative pharyngeal pressure decreased (by 37 29 %, P 0.005) compared with recovery , almost to a level observed at a TOF ratio of 0.5. Lung volume, respiratory timing , tidal volume, and minute ventilation remained unchanged after neostigmine / glycopyrrolate injection . Conclusion : Neostigmine / glycopyrrolate , when administered after recovery from neuromuscular block , increases upper airway collapsibility and impairs genioglossus muscle activation in response to negative pharyngeal pressure. Reversal with acetylcholinesterase inhibitors may be undesirable in the absence of neuromuscular blockade . Napoli SIA 2013

87. Representative recording of main variables from an awake healthy volunteer before partial neuromuscular blockade (baseline), during impaired neuromuscular transmission with a target train -of- four (TOF) ratio of 0.5, after spontaneous recoveryof the TOF ratio to unity , and during measurements initiated 2 min after injection of neostigmine (0.03 mg/kg) and glycopyrrolate ( 0.0075 mg/kg). A) Mask pressure at 2 cm H2O. Phasic ( respiratory ) genioglossus activity is very low while breathing near atmospheric pressure. During impaired neuromuscular transmission , no flow limitation is observed at this mask pressure. (B) Same volunteer during a negative pressure challenge (20 cm H2O). Before partial neuromuscular blockade , phasic genioglossus activity is markedly increased compared with breathing near atmospheric pressure. During partial neuromuscular blockade , phasic genioglossus activity is markedly increased compared with breathing at atmospheric pressure. However , the magnitude of the compensatory increase in genioglossus activity in response to negative pharyngeal pressure is impaired , and flow limitation is observed . After spontaneous recovery of the TOF ratio to unity , the compensatory phasic genioglossus activity is restored . Injection of neostigmine / glycopyrrolate attenuates the increase in genioglossus activity , and the changes observed attain similar values as those seen with partial neuromuscular blockade with a TOF ratio of 0.5. Napoli SIA 2013

88. Upper airway closing pressure significantly increased during partial neuromuscular blockade and was still abnormal even with recovery of the TOF ratio to unity (i.e. , before injection of neostigmine / glycopyrrolate ) ( P 0.01 vs.baseline ). However , upper airway closing pressure significantly increased after injection of neostigmine / glycopyrrolate . Upper airway critical closing pressure ( Pcrit ) in awake healthy volunteers at baseline before neuromuscular blockade , with impaired neuromuscular transmission and a target train -of- four (TOF) ratio of 0.5, after spontaneous recovery of the TOF ratio to unity , and after injection of neostigmine / glycopyrrolate Napoli SIA 2013

89. The genioglossus activity is presente as a percentage of maximal activity ( observed when the volunteer pressed his tongue with maximum strength against his teeth with the mouth closed ). Genioglossus activity evoked in response to negative pressure challenges isimpaired with neuromuscular blockade . The compensatorygenioglossus response to a pressure drop is restored after return of the TOF ratio to unity . After administration ofneostigmine / glycopyrrolate , genioglossus activity in response to negative airway pressure is markedly and significantly decreased . Genioglossus muscle activity as a function of negative mask pressure with neuromuscular blockade at a target TOFratio of 0.5 (open squares ), after spontaneous recovery of the TOF ratio to unity ( solid squares ), and after injection of neostigmine / glycopyrrolate Napoli SIA 2013

90. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Herbstreit F , Zigrahn D, Ochterbeck C, Peters J , Eikermann M. Anesthesiology . 2010 ;113(6):1280-8. Administration of neostigmine / glycopyrrolate , when administered after spontaneous recovery of neuromuscular function , in a dose similar to that recommended , and in routine clinical use, led to a significant increase in Pcrit and thus increased airway collapsibility in healthy volunteers . The increase in airway collapsibility was of a magnitude comparable with neuromuscular blockade with a TOF ratio of 0.5 . Furthermore , the normal compensatory activation of the genioglossus muscle in response to airway negative pressure challenges was blunted after administration of neostigmine / glycopyrrolate (i.e. , neostigmine / glycopyrrolate evoked a significant impairment of upper airway dilator muscle function ). Accordingly , whereas previous studies demonstrated airway compromise with residual neuromuscular blockade and thus a probable clinical need for reversal agents, theresults of this study reveal increased airway collapsibility as a result of neostigmine / glycopyrrolate , if given after recovery from neuromuscular transmission blockade . Napoli SIA 2013

91. Antagonismo dei miorilassanti Napoli SIA 2013

92. Presenza dei vapori…. Napoli SIA 2013

93. 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- ) Napoli SIA 2013

94. 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- ) Napoli SIA 2013

95. Insomma,continuare la soministraz del vapore ritarda la ripresa nm anche dopo rovesciamento…… Napoli SIA 2013

96. Neo vs edrofonio e profondità del blocco nm. Napoli SIA 2013

97. 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% Napoli SIA 2013

98. 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% ??? ? Napoli SIA 2013

99. Effect on Tof of 2 doses of neostigmine and edrophonium following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 37-43. Inspired enflurane concentration maintained at 0.5-1% Tof si ferma a 0.7!!! Napoli SIA 2013

100. Conclusione 1 La dose giusta di neostigmina è………… Meditate gente meditate……………… Napoli SIA 2013

101. 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. Napoli SIA 2013

102. Conclusione 2 E’ meglio somministrare gli antidoti quando la ripresa nm è iniziata È meglio cessare la somministrazione degli alogenati ( e monitorizzare la % et)……. Napoli SIA 2013

103. Anesthesiology . 2002 Jan;96(1):45-50. Efficacy of tactile-guided reversal from cisatracurium -induced neuromuscular block. Kirkegaard H, Heier T, Caldwell JE. Source Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA. [email protected] Abstract BACKGROUND: Because tactile evaluation is the most common form of clinical neuromuscular monitoring, this study examines the relative efficacy of antagonizing residual block at different levels of recovery of the tactile train-of-four (TOF) response. METHODS: Anesthesia was induced in 64 adults with 2-5 microg /kg fentanyl and 1-3 mg/kg propofol and maintained with fentanyl, propofol , and nitrous oxide. The tactile response of the adductor pollicis to TOF stimulation was evaluated at one arm, and the mechanomyographic response was recorded at the other. Patients received 0.15 mg/kg cisatracurium and were randomized to receive 0.07 mg/kg neostigmine on reappearance of the first (group I), second (group II), third (group III), or fourth (group IV) tactile TOF response (16 patients per group). Times from administration of neostigmine until the TOF ratio recovered to 0.7 (R0.7), 0.8 (R0.8), and 0.9 (R0.9) were measured. RESULTS: Data are presented as median with range in parentheses. R0.7 was 10.3 (5.9-23.4), 7.6 (3.2-14.1), 5.0 (2.0-18.4), and 4.1 (2.4-11.0) min in groups I, II, III, and IV, respectively (P < 0.05, group I > II, III, and IV, group II > IV). R0.8 was 16.6 (8.9-30.7), 9.8 (5.3-25.0), 8.3 (3.8-27.1), and 7.5 (3.0-74.5) min in groups I, II, III, and IV, respectively (P < 0.05, group I > II, III, and IV, group II > IV). R0.9 was 22.2 (13.9-44.0), 20.2 (6.5-70.5), 17.1 (8.3-46.2), and 16.5 (6.5-143.3) min in groups I, II, III, and IV, respectively (no intergroup differences). Ten minutes after neostigmine, a TOF ratio of 0.7 or greater was achieved in 50, 75, 88, and 93% of patients in groups I, II, III, and IV, respectively (P < 0.05 group I > II, III, and IV). At 30 min, a TOF ratio of 0.9 or less was observed in 21, 13, 13, and 7% of patients in groups I, II, III, and IV respectively (no intergroup differences). CONCLUSIONS: To achieve rapid (within 10 min) reversal to a TOF ratio of 0.7 in more than 87% of patients, three or four tactile responses should be present at the time of neostigmine administration. It was not possible within 30 min to achieve a TOF ratio of 0.9 in all patients, regardless of the number of tactile responses present at neostigmine administration Napoli SIA 2013

104. Napoli SIA 2013 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.

105. Napoli SIA 2013 Time from neostigmine administration to TOFR 0.70

106. Napoli SIA 2013 Time from neostigmine administration to TOFR 0.80

107. Napoli SIA 2013 Time from neostigmine administration to TOFR 0.90

108. Napoli SIA 2013 MMG magnitude of the first TOF twitch(T1) measured at the reappearance of each of the 4 tactile TOF responses.

109. Napoli SIA 2013 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 .

110. Time to tof 0.9 after neostigmine 0.07 mg/kg + glycopirrolate when tactile tof is 1,2,3,4( groups ) Kyo S. Kim , MD, PhD , Mi A. Cheong , MD, PhD , Hee J . Lee, MD, and Jae M. Lee,. Tactile Assessment for the Reversibility of Rocuronium - Induced Neuromuscular Blockade During Propofol or Sevoflurane Anesthesia . Anesth Analg 2004;99:1080 –5) Napoli SIA 2013 rocuronium 0.6 mg/kg and maintained with rocuronium 0.1 mg/kg given every time the height of first twitch (T1) in TOF recovered to approximately 15% of Tc obtained before induction of neuromuscular blockade .

111. Conclusione 3 With neostigmine it is impossible to obtain a tof 0.90 within 10 min. Napoli SIA 2013

112. Effetti collaterali degli anti AchE Napoli SIA 2013

113. Effetti fisiologici della presenza di Ach Bradicardia Salivazione Iperperistalsi Secrezioni bronchiali Napoli SIA 2013

114. 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;48:305-07. Purpose: To describe a heart transplant recipient who developed asystole after administration of neostigmine which suggests that surgical dennervation of the heart may not permanently prevent significant responses to anticholinesterases. Clinical features: A 67-yr-old man, 11 yr post heart transplant underwent left upper lung lobectomy. He developed asystole after intravenous administration of 4 mg neostigmine with 0.8 mg glycopyrrolate for reversal of the muscle relaxant. He had no history of rate or rhythm abnormalities either prior to or subsequent to the event. Conclusion: When administering anticholinesterase medications to heart transplant patients, despite surgical dennervation, one must be prepared for a possible profound cardiac response. Napoli SIA 2013

115. 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. Napoli SIA 2013

116. 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. Neostigmine- or pyridostigmine-induced IP1 accumulation was inhibited by 4-DAMP. Conclusions: The data suggest that anti-ChE drugs activate the M3 receptors at the tracheal effector site. Napoli SIA 2013

117. Schema delle afferenze parasimpatiche a livello tracheale Napoli SIA 2013

118. 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 Napoli SIA 2013

119. NEOSTIGMINE AND PONV Napoli SIA 2013

120. Tramèr, M. R. Fuchs-Buder, T..Omitting antagonism of nm block:effect on PONV and risk of residual paralysis.A systematic review.BJA 1999;82:379-386 A systematic search (MEDLINE, EMBASE, Biological Abstracts, Cochrane library, reference lists and hand searching; no language restriction, up to March 1998) was performed for relevant randomized controlled trials. In eight studies (1134 patients), antagonism with neostigmine or edrophonium was compared with spontaneous recovery after general anaesthesia with pancuronium, vecuronium, mivacurium or tubocurarine. On combining neostigmine data, there was no evidence of an antiemetic effect when it was omitted. However, the highest incidence of emesis with neostigmine 1.5 mg was lower than the lowest incidence of emesis with 2.5 mg. These data suggested a clinically relevant emetogenic effect with the higher dose of neostigmine in the immediate postoperative period but not thereafter. Numbers-needed-to-treat to prevent emesis by omitting neostigmine compared with using it were consistently negative with 1.5 mg, and consistently positive (3–6) with 2.5 mg. There was a lack of evidence for edrophonium. In two studies, three patients with spontaneous recovery after mivacurium or vecuronium needed rescue anticholinesterase drugs because of clinically relevant muscle weakness (number-needed-to-harm, 30). Omitting neostigmine may have a clinically relevant antiemetic effect when high doses are used. Omitting antagonism, however, introduces a non-negligent risk of residual paralysis even with short-acting neuromuscular blocking agents. Napoli SIA 2013

121. Watcha MF, Safavi FZ, McCulloch DA, et al. Effect of antagonism of mivacurium-induced neuromuscular block on postoperative emesis in children. Anesth Analg 1995; 80:713-7. * * Napoli SIA 2013

122. Ding Y,Fredman B, White PF.Use of mivacurium during laparoscopic surgery:effect of reversal drungs on postoperaive recovery.Anesth Analg 1994; 78:450–4 outpatient laparoscopic tubal ligation 60 healthy, nonpregnant women. midazolam / fentanyl/tps succ 1 mg/kg (Group I) vs mivacurium 0.2 mg/kg (Groups II and III) Anesthesia maintained with isoflurane (0.5%-2% +67% N2O Muscle relaxation maintained in all three groups with intermittent bolus doses of mivacurium, 2–4 mg, IV. In Group III, residual neuromuscular block reversed with neostigmine 2.5 mg +glycopyrrolate, 0.5 mg, Napoli SIA 2013

123. Effetti collat dello studio di Ding et al. * * * * Napoli SIA 2013

124. Risk of omitting neostigmine…. Residual paralysis!!! Napoli SIA 2013

125. Comportamento suggerito per l’antagonismo dei miorilassanti a lunga e media durata di azione secondo le risposte al Tof TOF esaurimento farmaco dose Twitch visibili nessuno Posponi antagonismo finchè almeno 1 o 2 contrazioni visibili!! 1-2 ++++ neostigmina 0.07 mg/kg 3-4 +++ neostigmina 0.04 mg/kg 4 ++ edrofonio 0.5 mg/kg 4 +/- edrofonio 0.25 Napoli SIA 2013

126. Time from administration of neostigmine or placebo/spontaneous recovery to recovery of the TOF ratio 0.7, 0.8 or 0.9 in non- sugammadex studies Napoli SIA 2013

127. Benefici attesi con Sugammadex Aumentata sicurezza per I pazienti Aumentata sicurezza in anestesia e chirurgia Ridotta incidenza ( eliminazione ) del blocco nm residuo Aumentata efficienza Benefici economici per accelerazione della ripresa,turnover + rapido ? Napoli SIA 2013

128. Napoli SIA 2013

129. Napoli SIA 2013

130. Napoli SIA 2013

131. Napoli SIA 2013 Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-81 - Double burst stimulation (DBS. The stimulus consists of two short bursts of 50 Hz tetanic stimulation , separated by 750 ms 52 healthy patients undergoing surgery were studied . For both stimulation patterns the frequencies of manually detectable fade in the response to stimulation were determined and compared at various electromechanically measured TOF ratios . A total of 369 fade evaluations for DBS and TOF were performed . : AB

132. Napoli SIA 2013 Probability of being within defined TOFR intervals when different clinical fade evaluations are given ( Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-81)

133. Napoli SIA 2013 Dbs 3-3 Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-81) Fade frequencies with DBS more frequent than with TOF Absence of fade with tof implies a 52% probability than tof >0.60 absence of fade with dbs implies a tof >0.60 in 91% of cases only tOFR <0.40 can be assessedd manually therefore,evaluation of DBS is relevant only when there is no fade to tof

134. Napoli SIA 2013 Conclusions: Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-81) absence of fade to DBS normally excludes severe residual nm blockade(tofr<0.60) BUT DOES NOT NECESSARILY INDICATE ADEQUATE CLINICAL RECOVERY.

135. Napoli SIA 2013

136. Napoli SIA 2013 Viby-Mogensen J , Jensen NH, Engbæk J , Ørding H, Skovgaard LT, Chæmmer-Jørgensen B. Tactile and visual evaluation of response to train -of- four nerve stimulation . Anesthesiology 1985; 63:440-3. Diaz/ tps /N2O 66%/ haloth 0.75-1.5% IOT with SCC , then panc simult MMG in one arm & visual / tactile evaluation in the opposite. Experienced and ( inexperienced ) anesthesiologists 6 different TOFR from every patient

137. Napoli SIA 2013 Viby-Mogensen et al Tactile and visual evaluation of response to train -of- four nerve stimulation . Anesthesiology 1985; 63:440-3.

138. Napoli SIA 2013 Threshold fade by 3 very experienced observers ( Viby-Mogensen et al. Tactile and visual evaluation of response to train -of- four nerve stimulation . Anesthesiology 1985; 63:440-3 )

139. Napoli SIA 2013 Threshold fade by 3 very experienced observers ( Viby-Mogensen et al. Tactile and visual evaluation of response to train -of- four nerve stimulation . Anesthesiology 1985; 63:440-3.)

140. Napoli SIA 2013 Which is the TOFR level that can be reliably detected visually by observing tetanic fade of the AP in response to 100-Hz, 5-s tetanus in anesthetized patients.?

141. RESIDUAL PARALYSIS WITH/OUT MONITORING Napoli SIA 2013

142. FINAL QUESTION 1: Does qualitative neuromuscular monitoring reduce the risk of residual block ? NO Napoli SIA 2013

143. 100 Hz visual assessment seems to be highly sensitive in evaluating residual paralysis , as the absence of RF100 Hz visual fading at the AP is compatible with a TOF ratio >0.85 Napoli SIA 2013 Baurain et al.Visual Evaluation of Residual Curarization in Anesthetized Patients Using One Hundred -Hertz, Five -Second Tetanic Stimulation at the Adductor Pollicis Muscle . Anesth Analg 1998; 87:185–9

144. Residual block in patients monitored with AMG Mortensen Gatke Murphy TOF watch 5.3 3 4.5 No monit 50 17 30 Napoli SIA 2013

145. Final question 2: Does quantitative neuromuscular monitoring reduce the risk of residual block ? It reduces but does not eliminate residual block Napoli SIA 2013

146. But ..... Despite high quality studies demonstrating a beneficial effect of quantitative monitoring on the incidence of PORC , few clinicians routinely use this type of monitoring . 22.7% USA ( Naguib et al , Anesth Analg 2010;1111:110- 9) 35% Italy ( Della Rocca et al, Minerva Anestesiol . 2012 Jul;78(7):767-73 . Neuromuscular block in Italy : a survey of current management. Della Rocca G, Iannuccelli F, Pompei L, Pietropaoli P, Reale C, Di Marco P Napoli SIA 2013

147. Conclusion s Until neuromuscular block during surgery is not routinely monitored with obiective means (MMG,AMG...) residual paralyss would continue and contribute to postoperative complications ! Napoli SIA 2013