Come Evitare la paralisi residua e

vivere felici :il sugammadex.

C.Melloni

Libero professionista

Napoli SIA 2013

RESIDUAL NEUROMUSCULAR BLOCK

Napoli SIA 2013

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

Napoli SIA 2013

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

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

TOFR=D/A

Napoli SIA 2013

Napoli SIA 2013

Napoli SIA 2013

Innervator Fisher & Paykel e TOfWatch Organon

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 lift

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

Napoli SIA 2013

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

POST OPERATIVE RESIDUAL CURARIZATION

PORC

Napoli SIA 2013

POSTOPERATIVE RESIDUAL PARALYSIS

PORP

Napoli SIA 2013

POSTOPERATIVE RESIDUAL NEUROMUSCULAR BLOCKADE OR WEAKNESS

PO RE NMB ??

Napoli SIA 2013

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

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

DtcGallapanc

vari

Atrac 0

panc

Atrac 0galla

Pancvecu Panc

vecu

panc

panc

panc

Tof<70

Tof <90

PORC % nella metanalisi di Naguib ;parte II

Napoli SIA 2013

Bissing

er 2

000

panc

Bissing

er 2

000

vecu

Ballar

d 20

00 v

ecu

Hayes

200

1 ve

cu

Hayes

200

1atra

c

Hayes

200

1 ve

cu

Hayes

200

1 ro

cu

Hayes

200

1 at

rac

Hayes

200

1 ro

cu

KIM 2

002

vecu

Kim 2

002

rocu

gark

e 20

02 ro

cu

Garke

200

2 ro

cu

Camm

u 20

02 c

isatra

c

Camm

u 20

02 ro

cu

Dedba

ene

2003

atra

c

Deabe

ne 2

003

vecu

Debae

ne 2

003

rocu

Kopm

an 2

004

cisat

rac

Kopm

an 2

004

rocu

Mur

phy

2005

rocu

Ballar

d 20

05 in

term

edia

Kopm

an 2

005

cisat

rac

Kopm

an 2

005

rocu

0

10

20

30

40

50

60

70

80

90

100

tof <0.70

tof < 0.90

Residual Paralysis at the Time of Tracheal ExtubationGlenn 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 usingstandard clinical criteria :(5-s head lift

or hand grip, eye opening on command,negative inspiratory force more than 20

cmH2 O, or vital capacity breath 15 cc/kg)

and peripheralnerve stimulation (no evidence of fade

with TOFor tetanic stimulation [50 Hz]). A 5-s

head lift (or handgrip) and the observation of an absence

of fade withperipheral nerve stimulation were the

minimal requirements

Nm block maintained at TOF 1-2

12% only with tof>0.9

120 pts

Residual Paralysis at the Time of Tracheal ExtubationGlenn 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

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

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

Napoli SIA 2013

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

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

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??

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

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

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.

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.

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 )?

Napoli SIA 2013

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

Chemorec.perif

Chemrecett.centr SNC

Ipossia

ipercapnia iperventilazione

Napoli SIA 2013

Corpi carotidei

Sito nicotinico

Sito muscarinico

nmb

atropina

ipossia

Napoli SIA 2013

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

Napoli SIA 2013

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

Napoli SIA 2013

The Incidence and Mechanisms of pharyngeal and Upper Esophageal Dysfunction in Partially Paralyzed humans.Eva Sundrnan,H anne Witt, Rolf

Olsson, Olle Ekberg, SRichard 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

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

ms

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

ms

Resting tension of the upper esophageal sphincter

Pharyngeal constrictor muscle function

Napoli SIA 2013

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 larynxNapoli SIA 2013

RESIDUAL NEUROMUSCULAR BLOCK AFFECTS PULMONARY FUNCTION

Napoli SIA 2013

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

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

Heier T,. Caldwell,JE. Feiner JR, Liu, L, Ward, T, B,. Wright PMC.Relationship between Normalized Adductor PollicisTrain-of-four Ratio and Manifestations of

ResidualNeuromuscular 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

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

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

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. matthais.eikermann@uni-essen.de 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

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

Muscle function and tofr in 12 partially paralyzed volunteersAnesthesiology. 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.

inabili

ty to

susta

in h

ead lift

>5 sec

iabili

ty to

seal m

outhpie

ce

inabili

ty to

sw

allow

norm

ally

fade o

f contra

ction v

isib

le

upper airw

ay obstru

ction

0

2

4

6

8

10

12

tof 0.5tof 0.8tof 1

Num

Napoli SIA 2013

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

T1-weighted spin echo magnetic

resonance midsagittal image of a

subject before neuromuscular

blockade (baseline

Napoli SIA 2013

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 fromneuromuscular blockade, end-

inspiratory volume was significantly

greater than end-expiratory volume. End-inspiratory

volume decreasedsignificantly during

partial neuromuscular

blockade, and was even lower

than end-expiratory

upper airway volume at a TOF ratio

of 0.5.

Napoli SIA 2013

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 significantlyboth in the

retroglossal and

retropalatal part of

the upper airway, butwas no longer

significantly different from baseline values

with recoveryof 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

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 wassignificantly greater in the retropalatal area compared with the retroglossal

area.

Napoli SIA 2013

Minimum cross-sectional area at end inspiration of the retroglossaland retropalatal part of the upper airway. Measurements during

quiet breathing before neuromuscular blockade (baseline) at a steadystateTOF ratio of 0.5 and 0.8, after recovery of the TOF ratio to 1.0,

and 15 min later.

During neuromuscular

blockade, airway crosssectionalarea decreased significantly in

both regions of the upper airway

and recovered to baseline values with a TOF ratio of unity. The

smallestcross-sectional area of

the retropalatal area was significantly less than

the smallest cross-sectional area of the

retroglossal area of the upperairway.

Napoli SIA 2013

Genioglossus function

Napoli SIA 2013

Napoli SIA 2013

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

. 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

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.,airwayintegrity is impaired

Napoli SIA 2013

.Genioglossus activity increases markedly and significantly as negativepressure is applied. However, the magnitude of this effect

is significantly attenuated with partial neuromuscular blockade

Napoli SIA 2013

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 partialEikermann 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

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

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

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

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

.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

Napoli SIA 2013

MA CHE CI IMPORTA DEL TOFR 0.90?

Viby Mogensen et al,AAS 1997

• 693 paz.randomizzati,cieco

• chir elettiva

• monitoraggio periop con Myotest e Tof

• confronto fra 1-5-2 ED95 diatrac,vecu,panc.

• Antagonismo se necessario;

• estubaz a tof eguale, tattile e resp adeguata.

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

trasferimento

0

5

10

15

20

25

30

35

40

45

Tof <0.70 tof<0.40

pancatracvecu

Andamento temporale del tof <0.80 nella RR

05

101520253035404550

0 5 10 15 20 30 40 50

min

% t

of<

0.8

0

pancatracvecu

Postoperative pulmonary complications

0

5

10

15

20

%

popc popc conbloccoresiduo

popc senzabloccoresiduo

pancvecu

atrac

pancvecuatrac

Popc secondo il tipo di chirurgia

0

2

4

6

8

10

12

14

16

%

popc

addomortopginecol

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

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 values19(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 PORP7,8,19(B)21(C).

   

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

Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery

room discharge.

Napoli SIA 2013

Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery

room discharge.

Napoli SIA 2013

DO WE ALWAYS NEED TO REVERSE NMB?

Napoli SIA 2013

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

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

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

nearatmospheric 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, phasicgenioglossus activity is markedly increased compared with breathing near atmospheric

pressure. During partial neuromuscularblockade, phasic genioglossus activity is markedly increased compared with breathing at atmospheric

pressure. However, themagnitude 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 activityis restored. Injection of neostigmine/glycopyrrolate attenuates the increase in genioglossus activity,

and the changes observedattain similar values as those seen with partial

neuromuscular blockade with a TOF ratio of 0.5.

Napoli SIA 2013

Upper airway closing pressure significantly increased during partial neuromuscular blockade and wasstill 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 significantlyincreased 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

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

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

Antagonismo dei miorilassanti

Napoli SIA 2013

Presenza dei vapori….

Napoli SIA 2013

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

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

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

Napoli SIA 2013

Neo vs edrofonio e profondità del blocco nm.

Napoli SIA 2013

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

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

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

Conclusione 1

La dose giusta di neostigmina è…………

Meditate gente meditate………………

Napoli SIA 2013

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

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

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. hanskirkegaard@dadlnet.dk

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

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.

Napoli SIA 2013

Time from neostigmine administration to TOFR

0.70

I twitch II twitch III twitch IV twitch0.00

5.00

10.00

15.00

20.00

25.00

mediana

Napoli SIA 2013

Time from neostigmine administration to TOFR 0.80

I twitch II twitch III twitch IV twitch0

10

20

30

40

50

60

70

80

mediana

Napoli SIA 2013

Time from neostigmine administration to TOFR 0.90

I twitch II twitch III twitch IV twitch0

10

20

30

40

50

60

70

80

mediana

Napoli SIA 2013

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

tactile TOF responses.

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.

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 Tcobtained before induction of neuromuscular

blockade.

Conclusione 3

With neostigmine it is impossible to obtain a tof 0.90 within 10 min.

Napoli SIA 2013

Effetti collaterali degli anti AchE

Napoli SIA 2013

Effetti fisiologici della presenza di Ach

Bradicardia Salivazione Iperperistalsi Secrezioni bronchiali

Napoli SIA 2013

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

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

Pericoli degli antiAchE:broncocostrizione Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K.

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

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

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

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

Napoli SIA 2013

Schema delle afferenze parasimpatiche a livello tracheale

Napoli SIA 2013

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

NEOSTIGMINE AND PONV

Napoli SIA 2013

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

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

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

Effetti collat dello studio di Ding et al.

*

*

*

*

Napoli SIA 2013

Risk of omitting neostigmine….

Residual paralysis!!!

Napoli SIA 2013

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

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

tof 0,9 Adamus tof0,9 Barrio tof 0,9 Adamus tof 0,9 Bevan tof 0,8 Della Rocca 0

10

20

30

40

50

60

rocu 0,6+neorocu0,6 spontrocu 0,9+neorocu 0,9 spont

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

Napoli SIA 2013

tactile assessmenttactile assessment

TetanusTetanus

DBSDBS

TOFTOF

Napoli SIA 2013

Clinical signsClinical signscorrelation with residual forcecorrelation with residual force

patient cooperation!patient cooperation!

tonguedepressorclenching

tonguedepressorclenching

head lift> 5 sechead lift> 5 sec

arm or leglift> 5 secarm or leglift> 5 sec

sustainedhand gripstrenght

sustainedhand gripstrenght

Napoli SIA 2013

clinical signsclinical signsreliable vs not reliablereliable vs not reliable

TV normalTV normal unreliableunreliable

Neg Press < 25 mmHgNeg Press < 25 mmHgunreliableunreliable

Neg press < 50 mmHgNeg press < 50 mmHgreliablereliable

coughcough unreliableunreliable

eye openingeye openingunreliableunreliable

tongue protrusiontongue protrusionunreliableunreliable

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

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

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)

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

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.

Napoli SIA 2013

Meccanomiographic vs tactileevaluation

Meccanomiographic vs tactileevaluation

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

qualitative tofevaluation

qualitative tofevaluation

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

qualitative DBSevaluation

qualitative DBSevaluation

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

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

Napoli SIA 2013

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

Anesthesiology 1985; 63:440-3.

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)

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.)

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.?

RESIDUAL PARALYSIS WITH/OUT MONITORING

TOF MONITORING NO MONIT0

10

20

30

40

50

60

70

80

PEDERSENSHORTEN FRUERGAARD

Napoli SIA 2013

FINAL QUESTION 1:

Does qualitative neuromuscular monitoring reduce the risk of residual block?

–NO

Napoli SIA 2013

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

Residual block in patients monitored with AMG

Mortensen Gatke Murphy

TOF watch 5.3 34.5No monit 50 17 30

Napoli SIA 2013

Final question 2:Does quantitative neuromuscular monitoring reduce the risk of residual block?

It reduces but does not eliminate residual block

Napoli SIA 2013

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

Conclusions

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