Nora e reversal colorato slideshare; NaPoli i SIA 2016

Nora e reversal della
miorisoluzione.
C.Melloni
Libero professionista
Napoli SIA 2016

Assenza di conflitto di
interessi
 Non ho alcun interesse commerciale o
finanziario nei farmaci citati nella
presente letttura nè ho ricevuto fondi per
questa lettura .
Napoli SIA 2013

Complicanze gravi durante
MRI
 Totale pazienti trattati con MRI:
 2.045.954
 33 arresti cardioresp.
 11 decessi
 16.1/1.000.000 di MRI,con 5,3
decessi/1.000.000 di MRI
Napoli SIA 2013

Dati su 182 MRI USA
(Schiebler M,Kaut-Watson C,Williams DL Both sedated and critically ill
require monitoring during MRI(In Vivo Research,1992-2000)
Napoli SIA 2013
0
50
100
150
200
250
300
350
tot
paz sedati/magnete/anno
sedaz p.os/magnete/anno
sedaz ev/magnete/anno
monitorati/magnete/anno
3010+/-188
pazient/anno

Anaesthesia for magnetic resonance imaging: a survey of current practice in the UK
and Ireland.
Napoli SIA 2013
McBrien M. E. et al. Anaesthesia 55:737-743, 2000
 Postal questionnaire was sent to 120 MRI units in UK and 6 in Republic of
Ireland
 100 (79%) responses:
» 46 units had an anaesthetic service (36 units on a regular basis, 10 on
demand)
12
8
5
0
2
4
6
8
10
12
N°Units
Radiologists Paediatricians Both
0
5
10
15
20
25
GAA GPA NAP NA
21
15
9
7
N°Units
AnaesthetistGAA: General Adult Anaesthetist
GPA: General Paediatric
NAP: Neuroanaesthetist with regular Paediatric practice
NA: Neuroanaesthetist with no regular paediatric practice
Sedation provided by nonanesth personnel Sedation provided by anesth,personnel

Cote,C,Charles,J,Helen,W,Notterman,DA,Daniel A.,Weinberg
JA,Mc CLoskey C. Adverse sedation events in pediatrics ;analysis
of medication used for sedation.
Pediatrics 106:633-64.:2000.
Napoli SIA 2013
not harmed(+
extra Hosp stay)
death
permanent
neurol injury
118 cases from the adverse drug reporting
System of the FDA,US Pharmacopeia and a results of a survey of
pediatric specialists

Allocation of medication related
adverse events
Napoli SIA 2013
drug interaction
drug overdose
premature discharge
prescr/transcription error
inadeq understanding of adm.medications
adm by unsupervised technician
parent adm

Single drug administration associated with death
or permanent neurologic injury
Napoli SIA 2013
0 2 4 6 8
chloral hydr
metoex
thiop
pentobarb
ket
midaz
num

Relationship of interest of
negative outcome
Napoli SIA 2013
 No with general category of drug
 No with route of administration
 Yes with 3 or > sedation medications
 12 pts suffered at home or in
auto;chloral hydrate most frequently
involved
 Dental specialists
overrepresented:39%!

Complicazioni delle
endoscopia digestiva
 0.13-0.08%
 Mortalità 0.7-1/10.000
 50% delle KO e 65% dei decessi dovuti
a probl cardioresp
Napoli SIA 2013

1989 ASGE Survey of Endoscopic sedation and monitoring
practice(Gastrointest Endoscopy 1990;36:s13-18)
Napoli SIA 2013
0 20 40 60 80 100
>75%
50-75%
up to 33%
none
% dei paz sedati durante endoscopia
UK
ASGE

problemi durante e dopo la procedura
LUGAY M,OTTO G,KONG M,MASON DJ, WILETS I. Recovery Time and Safe
Discharge of Endoscopy Patients After Conscious Sedation .Gastroenterology Nursing 19;1996:194-200
Napoli SIA 2013
0
5
10
15
20
25
30
35
40
45
%
pain hypertensione Hypotension bradycardia O2
desaturation
weakness abdom.pain dizziness
intraprocedure
adverse occurrences
postprocedure
adv.occurr.

Ko of endoscopic procedures.
Freeman ML, Timothy Hennessy J, Cass OW, Phelley AM. Carbon dioxide retention and oxygen
desaturation during gastrointestinal endoscopy. Gastroenterology 1993; 93: 331-339.Freeman ML. Sedation
and monitoring for gastrointestinal endoscopy. Gastrointest Endosc Clin N Am 1994; 94: 475-499.
Napoli SIA 2013
0
10
20
30
40
50
60
70
80
90
100
%
fentanyl midaz desaturaz need o2 ipetens tachic
egd
colonscopy
ercp

Anormalità resp.e anestesia topica
Mc Nicholas WS, Coffey M, Mc Donnel T, O'Regan R, Fitzgerald MX. Upper
airway obstruction during sleep in normal subjects after selective topical
oropharyngeal anesthesia. Am Rev Respir Dis 1987;135:1316-9
Napoli SIA 2013
0
2
4
6
8
10
12
14
16
18
20
controlli anest
orofaringea
anest.nasale
Apnea ostruttiva+
ipopnea
apnea
centrale+ipopnea
apnee e ipopnee
tot
9 normal subjects
20-28 y.

Saturazione O2 e premed con
BDZ
 SaO2 89-92%;
» Bell Scand J Gastroenterol 1990
 Ulteriore riduz durante introduz dello
strumento specie nei primi 3-4 min dopo
premed. (Lieberman Gastroenterology 1985)
 BDZ+oppioide O2 desat ancora + spiccata
(40%)+fattori di rischio (age>65,Cold…);
» Hart & Classen Endoscopy 1990)
» Cousins Scand J gastroenterol 1990)
Napoli SIA 2013

Fattori contributori alla desaturazione
in O2 durante endoscopia digestiva
 Ostruzione del faringe
 Compressione tracheale
 Distensione gastrica
 farmaci
 Anest loc
Napoli SIA 2013

Deaths in the dentists office
 References:
 (1) Lee HH et al, Trends in death
associated with pediatric dental sedation
and general anesthesia. Paediatr Anaesth.
2013 Aug;23(8):741-6.
 (2) Chicka MC et al, Adverse events during
pediatric dental anesthesia and sedation: a
review of closed malpractice insurance
claims. Pediatr Dent.2012 May-
Jun;34(3):231-8.Napoli SIA 2013

Sicurezza della NORA:
odontoiatria
Napoli SIA 2016
 Lee HH et al, Trends in death associated with pediatric dental sedation and general anesthesia.
Paediatr Anaesth. 2013 Aug;23(8):741-6.
 analisi di 25 morti di bambini per anestesia ,
effettuata nello studio dentistico ,di cui 17 in
sedazione
 Chicka MC et al, Adverse events during pediatric dental anesthesia and sedation: a review of closed
malpractice insurance claims. Pediatr Dent.2012 May-Jun;34(3):231-8.
 17 disastri :13 sedation, 3 AL da sola ,1 GA
 53% morte o danno cerebrale permanente

Lee HH et al, Trends in death associated with pediatric dental sedation and
general anesthesia. Paediatr Anaesth. 2013 Aug;23(8):741-6
 analisi di 25 morti di bambini per
anestesia , effettuata nello studio
dentistico ,di cui 17 in sedazione.
Napoli SIA 2013

Pediatric dental deaths by anesthesia
provider and age categories
Napoli SIA 2013
Lee HH et al, Trends in death associated
with pediatric dental sedation and
general anesthesia. Paediatr Anaesth.
2013 Aug;23(8):741-6

Pediatric dental deaths by anesthesia
provider and facility type
Napoli SIA 2013
Lee HH et al, Trends in death associated with
pediatric dental sedation and general anesthesia.
Paediatr Anaesth. 2013 Aug;23(8):741-6

Pediatr Dent. 2012 May-Jun;34(3):231-8.
Adverse events during pediatric dental anesthesia and sedation: a
review of closed malpractice insurance claims.
Chicka MC1, Dembo JB, Mathu-Muju KR, Nash DA, Bush HM
College of Dentistry, University of Kentucky, Lexington, KY, USA..
 malpractice claims di 2 assicurazioni professionali USA 1993-2007.
 17 disastri :13 isedation2, 3 AL da sola 1 iGA
 53% morte o danno cerebrale permanente
 Età media was 3.6anni;6 , 6 casi presente solo il dentista 2 2 AL sola
 overdoses Di LA in 41%
 Sede:ufficio del dentista 71% dei casi
 Delle 13 sedazioni,solo 1 monitorato.
 CONCLUSIONS:
 Very young patients (≤ 3-years-old) are at greatest risk during administration of
sedative and/or local anesthetic agents. Some practitioners are inadequately
monitoring patients during sedation procedures. Adverse events have a high chance
of occurring at the dental office where care is being provided
Napoli SIA 2013

Fox 40 Sacramento: “Dentist Charged in Death of
Patient After Trying to Extract 20 Teeth”
 A Connecticut dentist turned himself into Enfield
police on Tuesday in connection with the death of
one of his patients. Dr. Rashmi Chhotabhai Patel,
45, of Suffield, was charged with criminally negligent
homicide and tampering with evidence on Tuesday.
Judy Gan, 64, and her husband Michael arrived at
Enfield Family Dental, which is located at 71 Hazard,
for 20 teeth extractions, implants and grafts in
Februrary 2014.
Napoli SIA 2013

Children periodically die in dental offices due to complications of general anesthesia
or intravenous sedation. Links to recent reports include the following
 A 3-year-old girl dies in San Ramon, CA after a dental procedure in
July 2016.
 A 14-month-old child, scheduled to have 2 cavities filled, dies in an
Austin, TX dental office. The dentist and an anesthesiologist were both
present.
 A 6-year-old boy, scheduled to have teeth capped at a dental clinic,
has anesthesia and dies after the breathing tube is removed.
 Another 6-year-old boy, scheduled to have a tooth extracted by an oral
surgeon, dies after the oral surgeon administers general anesthesia.
Napoli SIA 2013

Colonscopia
 Adverse events during colonoscopy:2-3/1000 colon
 Perforazioni,sanguinamento,infezioni,probl
cardiovasc....
» Sethi A, Song LM.Adverse events related to colonic endoscopic mucosal resection and
polypectomy. Gastrointest Endosc Clin N Am. 2015 Jan;25(1):55-69.)
 Particolarmente a rischio per tutte le elencate
complicanze sono gli anziani,> 80 anni
» (Day LW1, Kwon A, Inadomi JM, Walter LC, Somsouk MAdverse events in older patients undergoing colonoscopy: a systematic
review and meta-analysis. Gastrointest Endosc. 2011 Oct;74(4):885-96.
 Warren JL1, Klabunde CN, Mariotto AB, Meekins A, Topor M, Brown ML, Ransohoff DF.
» Adverse events after outpatient colonoscopy in the Medicare populationAnn Intern Med. 2009 Jun 16;150(12):849-57, W152.
 .
Napoli SIA 2013

Bhananker SM, Posner KL, Cheney FW, et al. Injury and liability
associatedwith monitored anesthesia care: a closed claim analysis.
Anesthesiology2006; 104:228–234
Napoli SIA 2016

Closed claims NORA vs Sala op
NORA Sala op
Tipo di anestesia MAC 58% MAC 6%
Age >70 50% 19%
Eventi resp +++ +
Inadeguata ossigenaz/ventilaz 33% 2%
Napoli SIA 2013

Chang B1, Kaye AD, Diaz JH, Westlake B, Dutton RP, Urman RD.
Complications of Non-Operating Room Procedures: Outcomes From the National Anesthesia
Clinical Outcomes Registry.
J Patient Saf. 2015 Apr 7. [Epub ahead of print]
 National Anesthesia Clinical Outcomes Registry database was examined to compare OR to NORA
anesthetic complications and patient demographics.
 12,252,846 cases were analyzed, with 205 practices contributing information, representing 1494 facilities and 7767 physician providers. Year 2010-2013
 OP room vs NORA
 Nora ptaients plder> 50 (61.92% versus 55.56%, P < 0.0001).
 MAC ad (20.15%) and sedation (2.05%) more common in NORA
 locations. The most common minor complications were postoperative nausea and vomiting (1.06%), inadequate pain control (1.01%), and hemodynamic instability (0.62%).
The most common major complications were serious hemodynamic instability (0.10%) and upgrade of care (0.10%).
 There was a greater incidence of complications in cardiology and radiology
locations.
 Overall mortality was higher in OR versus NORA (0.04% versus
0.02%, P < 0.0001). Subcategory analysis showed increased
incidence of death in cardiology and radiology locations (0.05%).
 CONCLUSIONS:
 Non-OR anesthesia procedures have lower morbidity and mortality rates than OR procedures, contrary to some previously published studies. However, the increased
complication rates in both the cardiology and radiology locations may need to be the target of future safety investigations. Providers must ensure proper monitoring of
patients, and NORA locations need to be held to the same standard of care as the main operating room. Further studies need to identify at-risk patients and procedures that
may predispose patients to complications

Obbiettivi anestesiologici della
NORA
 Induzione rapida
 Risveglio rapido
 Assenza di sequele;dolore,PONV..
 Rapidità di ripresa:street fitness???

anestetico/analgesico/ipnotico/
miorilassante per la NORA
 Inizio di azione rapido
 Scomparsa rapida;
 Assenza di effetti prolungati
 Assenza di effetti cardiovascolari(liberazione di
istamina...);PA,FC,ECG...
 Assenza ( o quasi) di reazioni allergiche/anafilattiche
 Antagonismo rapido????o sua inutilità???
 Assenza di PORC per i miorilassanti....
Napoli SIA 2016

QUANDO SONO
NECESSARI/UTILI I
MIORILASSANTI???
Primo punto:

Gli scopi della intubazione
tracheale
 Garanzia del mantenimento della pervietà
delle vie aeree superiori;
 Protezione delle vie aeree da parte del
contenuto gastrico;
 Permettere la ventilazione artificiale
meccanica a pressione positiva;
 Permettere la aspirazione dell’albero
tracheobronchiale

Indicazioni all’intubazione
endotracheale
 Supporto alla ventilazione durante AG:
 Tipo di chirurgia...
 Sito operativo vicino/conflitto con vie aeree..
 Chir addominale,toracica,cardio..,neuro..
 Posizioni difficili:prona/lat...
 Chirurgia prolungata
 Paziente a rischio di aspirazione
polmonare;coma,trauma....
 Ventilazione in maschera difficile
 Necessità(anche presunta) di ventilaz postop.

Quali necessità e per quali
procedure ??
 Procedure nelle quali è necessaria/preferibile la AG,specie per assicurare
immobilità(RMN;neurrad interv,biopsie tac guidate)
 Bambini...ampio spettro di interventi.....
 Pazienti non cooperanti,claustrofobici,traumatizzati....
 Quando si deve stare distanti dal paziente?
 Radiazioni
 Posizione prona
 Oscurità
 Competizione per le vie aeree
 Durata difficile da predire
 La fine può essere però improvvisa,specie se non conosciamo
l’intervento......mantenere la comunicazione con lo
specialista,anzi,chiedere in anticipo........
 ....

gastroin
test

NEURORADIOLOGIA:
 Embolizzazione di aneurismi/malformazioni
vascolari
 Interventi stereotattici sotto monitoraggio
EEG/RMN/TAC.... Diagnostic imaging procedures
 MRI,Ciclotron :AV malformaz,pituitary
tumors,retinoblastomas.radiation painless,but
positioning may take hours.....head fixation painful
 Terapia radiante
 Brachiterapia
 Trauma cranico....

Sala di emodinamica/cardiologia
interventistica
 Rivascolarizzazione
percutanea.,angiografia,stent....
» (pazienti con distress
acuto,emodinamicamente instabili,
 Difetti interatriali e/o ventricolari(TEE)
 Defibrillatore impiantabile

gastroenterologia
 Diagnostica
 Terapeutica
 Ercp
 Varici.....

Trasporti;ambulanza,elicottero,aereo..
 Pazienti critici
 Interventistica stradale/terremoti,ecc.

Varie
 Odontostomatologia
 Centro ustioni
 Terapia elettroconvulsiva
 Litotrissia
 Ginecologia,fertilizzazione,isteroscopia,miomectomi
a
 Beware of situation whwere the anesthesioloogist
is callled after the intervention has starterd and the
patient found uncooperative.
 oculistica

APRIAMO UNA DISCUSSIONE SU
COME INTUBARE,CIOÈ CON QUALI
FARMACI? QUANDO?
ADIUVANTI.....?

 Incredibile ,ma vero,sull’argomento con quali
farmaci intubare e quando non c’è molto.....
 Forse non ci siamo posti il problema come
una priorità...ma non intubiamo solo noi
anestesisti..........
 E le condizioni/necessità sono molto varie:
» elezione in sala op(anestesista),emergenza in
PS(Psoccorsista),strada...(IP?Rian??)
» NORA(anestesista?)
» Arresto cardiaco:cardiologo?IP?medico???

Capacità di intubare
 Esperienza prima di
tutto.........OPERATORE
 Strumenti......lame,video....

INTUBATION WITH OR
WITHOUT MUSCLE
RELAXANTS???

[Comparison of the effects of remifentanil and remifentanil plus
lidocaine on intubation conditions in intellectually disabled patients].
Eyigor C, Cagiran E, Balcioglu T, Uyar M.
Braz J Anesthesiol. 2014 Jul-Aug;64(4):263-8
 Background and objectives: This is a prospective, randomized, single-blind study. We aimed to
compare the tracheal intubation conditions and hemodynamic responses either remifentanil or a
combination of remifentanil and lidocaine with sevoflurane induction in the absence of
neuromuscular blocking agents.
 Methods: Fifty intellectually disabled, American Society of Anesthesiologists I-II patients who
underwent tooth extraction under outpatient general anesthesia were included in this study. Patients
were randomized to receive either 2 􏰁g kg−1 remifentanil (Group 1, n = 25) or a combination of 2
􏰁g kg−1 remifentanil and 1 mg kg−1 lidocaine (Group 2, n = 25). To evaluate intubation conditions,
Helbo-Hansen scoring system was used. In patients who scored 2 points or less in all scorings,
intubation conditions were considered acceptable, however if any of the scores was greater than 2,
intubation conditions were regarded unacceptable. Mean arterial pressure, heart rate and peripheral
oxygen saturation (SpO2) were recorded at baseline, after opioid administration, before intubation,
and at 1, 3, and 5 min after intubation.
 Results: Acceptable intubation parameters were achieved in 24 patients in Group 1 (96%) and in 23
patients in Group 2 (92%). In intra-group comparisons, the heart rate and mean arterial pressure
values at all-time points in both groups showed a significant decrease compared to baseline values
(p = 0.000)
 Conclusion: By the addition of 2 􏰁g/kg remifentanil during sevoflurane induction, successful
tracheal intubation can be accomplished without using muscle relaxants in intellectually dis-
abled patients who undergo outpatient dental extraction. Also worth noting, the addition of 1
mg/kg lidocaine to 2 􏰁g/kg remifentanil does not provide any additional improvement in the
intubation parameters.

È meglio intubare con i
miorilassanti o no?
Siiiii...
 Però attenti al timing.......:possibilmente alla massima
profondità di blocco
» (monitoraggio!!!!) orbicularis oculi> pollice???
» Ma non diminuisce la frequenza di lesioni
» Mencke, T1, Echternach M, Plinkert PK, Johann U, Afan N, Rensing H,
Noeldge-Schomburg G, Knoll H, Larsen R. Does the timing of tracheal
intubation based on neuromuscular monitoring decrease laryngeal injury? A
randomized, prospective, controlled trial. Anesth Analg. 2006

Miorilassanti si/NO
 L’utilizzo dei miorilassanti migliora le condizioni per
intubazione e diminuisce le sequele locali
traumatiche
» Anesthesiology. 2003 May;98(5):1049-56.
Laryngeal morbidity and quality of tracheal
intubation: a randomized controlled trial.
Mencke T, Echternach M, Kleinschmidt S, Lux P, Barth
V, Plinkert PK, Fuchs-Buder T.
» Can J Anaesth. 2003 Feb;50(2):121-6. Muscle relaxation and increasing doses of propofol
improve intubating conditions. Lieutaud T1, Billard V, Khalaf H, Debaene B.
» Atrac + dosi crescenti di propof.

Mencke T, Echternach M, Kleinschmidt S, Lux P, Barth V, Plinkert PK, Fuchs-Buder
T. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled
trial. Anesthesiology. 2003 May;98(5):1049-56. .

Mencke T, Echternach M, Kleinschmidt S, Lux P, Barth V, Plinkert PK,
Fuchs-Buder T. Laryngeal morbidity and quality of tracheal intubation: a
randomized controlled trial. Anesthesiology. 2003 May;98(5):1049-56.

Wilcox SR, Bittner EA, Elmer J, Seigel TA, Nguyen NT, Dhillon A, et al. Neuromuscular
blocking agent administration for emergent tracheal intubation is associated with
decreased prevalence of procedure-related complications. Crit Care Med 2012;40:1808-
13
NMB si NMB no
Num of attempts:1 85% 78%
“ “ :3 + 1% 4%
Cormack Lehane 1 76% 62%
“ “ 2 16% 24%
“ “ 3 8% 11%
“ “ 4 1% 3%
Hypoxemia <80% 10.1% 17.4%
Airway complications 3.1% 8.3%
TI;intensivists

Benoit JL1, Gerecht RB2, Steuerwald MT2, leanMullan JT2.
Endotracheal intubation versus supraglottic airway placement in out-of-hospital
cardiac arrest: A meta-analysis. Resuscitation. 2015 Aug;93:20-6 .
 Out of hospital cardiac arrest patients:
intubation vs supraglottic
airway
 Better ROSC
 Better survival to hospital
admission
 More neurologically intact survival

From NAP4 ,pag 73,chapter 7
 Inadequate anaesthesia, muscle relaxants and
ventilation
 Light anaesthesia contributed to some events. In others severe airway
difficulty was encountered and the anaesthetist made strenuous efforts to
avoid administering muscle relaxants, even beyond the point of patient
harm.
 Recommendation: Where facemask or laryngeal mask anaesthesia is
complicated by failed ventilation and increasing hypoxia the anaesthetist
should consider early administration of further anaesthetic agent and or a
muscle relaxant to exclude and treat laryngospasm.
 Recommendation: No anaesthetist should allow airway obstruction and
hypoxia to develop to the stage where an emergency surgical airway is
necessary without having administered a muscle relaxant.

NAP 4
 panel considered that delay or avoidance of administering a
muscle relaxant in this scenario likely contributed to the adverse
event in at least three cases.(chapter 7,induction and
maintenance of anesthesia),pag 57
 Airway problems arose that appeared to be a consequence of
light anaesthesia. Prompt deepening of anaesthesia, and or use
of muscle relaxants was often delayed. In some cases delay
was until and beyond the time that patient harm
occurred.(Chapter 7,induction and maintenance of
anesthesia,pag 60)
 Recommendation: Even if it was not part of the initial airway
management strategy, if CIC V occurs and waking the patient
up is not an option, a muscle relaxant should be given before
determining the need to proceed to a surgical airway.(pag
211,appendix 5 ,recommendations at a glance )

Problema principale dei miorilassanti:
La paralisi residua postop:PORC ,
Assumendo che tutti i problemi dell intraop e utilizzo dei miorilassanti
siano risolti..........
» Difficoltà intubazione
» Anafilassi
» Aritmie...
» Costi....

LA PARALISI RESIDUA
POSTOP:PORC

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
vari
Atrac 0
panc
Atrac 0
galla
Panc
vecu Panc
vecu
panc
panc
panc
Tof<70
Tof <90

PORC % nella metanalisi di Naguib ;parte II
Napoli SIA 2013
0
10
20
30
40
50
60
70
80
90
100
tof <0.70
tof < 0.90

Naguib 2007 shows
situation of porc before
sugammadex,situation
changes today ?

( Ledowski T1, O'Dea , Meyerkort L, Hegarty M, von Ungern-Sternberg BS.
Postoperative Residual Neuromuscular Paralysis at an Australian Tertiary
Children's Hospital. Anesthesiol Res Pract. 2015;2015:410248.
 The incidence of RNMB (TOFr < 0.9) was overall 28.1%
 (Severe RNMB (TOF ratio < 0.7) was found in 2 patients
(6.5%) after both no reversal and neostigmine,
respectively.

Fortier LP1, McKeen D, Turner K, de Médicis É, Warriner B, Jones PM, Chaput A, Pouliot JF, Galarneau
A.The RECITE Study: A Canadian Prospective, Multicenter Study of
the Incidence and Severity of Residual Neuromuscular
Blockade.Anesth Analg. 2015 Aug;121(2):366-72..
 Adult patients undergoing open or laparoscopic abdominal surgery expected to last <4 hours
 ASA physical status I-III, and scheduled for general anesthesia with at least 1 dose of a nondepolarizing
neuromuscular blocking agent for endotracheal intubation or maintenance of neuromuscular relaxation were
enrolled in the study.
 Neuromuscular function was assessed using acceleromyography with the TOF-Watch SX.
 The attending anesthesiologist and all other observers were blinded to the TOF ratio (T4/T1) results.
 The primary and secondary objectives were to determine the incidence and severity of residual NMB (TOF ratio
<0.9) just before tracheal extubation and at arrival at the postanesthesia care unit (PACU).
 302 pts,. Data available for 241 patients at tracheal extubation and for 207 patients at PACU arrival.
 Rocuronium was the NMB agent used in 99% of cases.
 Neostigmine was used for reversal of NMB in 73.9% and 72.0% of patients with TE and PACU data,
respectively.
 The incidence of residual NMB was 63.5% (95% confidence interval, 57.4%-69.6%) at tracheal extubation and
56.5% (95% confidence interval, 49.8%-63.3%) at arrival at the PACU.
 In an exploratory analysis, no statistically significant differences were observed in the incidence of residual NMB
according to gender, age, body mass index, ASA physical status, type of surgery, or comorbidities (all P > 0.13).
 CONCLUSIONS:
 Residual paralysis is common at tracheal extubation and PACU arrival, despite
qualitative neuromuscular monitoring and the use of neostigmine. More effective
detection and management of NMB is needed to reduce the risks associated with residual NMB.

Incidence of residual nmb
The RECITE StudyFortier LP1, McKeen D, Turner K, de Médicis É,
Warriner B, Jones PM, Chaput A, Pouliot JF, Galarneau A.The RECITE Study: A Canadian
Prospective, Multicenter Study of the Incidence and Severity of Residual Neuromuscular
Blockade.Anesth Analg. 2015 Aug;121(2):366-72.
45%!!

McLean DJ1, Diaz-Gil D, Farhan HN, Ladha KS, Kurth T, Eikermann M.Dose dependent
association between intermediate acting neuromuscular blocking agents and postoperative
respiratory complications Anesthesiology. 2015 Jun;122(6):1201-13
 Studio retrospettivo di 48499 paz in 5 anni
 Paz con le dosi più elevate di nmb hanno
dimostrato un aumento del rischio di Ko
resp.
 Paz che hanno ricevuto le dosi più elevate
di AchEI(> 60 microgr/kg) per antag dei
nmb hanno mostrato un rischio aumentato
di KO resp postop,mentre le dosi
appropriate hanno diminuito le Ko

NMB come multipli della dose
ED 95

Anesthesiol Res Pract. 2015;2015:410248. doi: 10.1155/2015/410248. Epub 2015 May 10.
Postoperative Residual Neuromuscular Paralysis at an Australian Tertiary
Children's Hospital.
Ledowski T1, O'Dea , Meyerkort L2, Hegarty M3, von Ungern-Sternberg BS4
 Australian tertiary pediatric center
 All children receiving NMBA during anesthesia were
included over a 5-week period at the end of 2011
 At the end of surgery, directly prior to tracheal
extubation, TOFR was assessed quantitatively.
 RNMB was 28.1% overall (without reversal: 19.4%;
after neostigmine: 37.5%; n.s.).
 Severe RNMB (TOF ratio < 0.7) in 6.5% after both no
reversal and neostigmine,

 Br J Anaesth. 2015 Nov;115(5):743-51. doi: 10.1093/bja/aev104. Epub 2015 May 2.
 Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study.
 Brueckmann B1, Sasaki N1, Grobara P2, Li MK3, Woo T3, de Bie J3, Maktabi M4, Lee J4, Kwo J5, Pino R5, Sabouri AS1,
McGovern F6, Staehr-Rye AK7, Eikermann M8.
 :
 This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex
reduced the incidence of residual blockade and facilitated operating room discharge readiness.
 METHODS:
 Adult patients undergoing abdominal surgery received rocuronium, followed by randomized allocation to sugammadex (2
or 4 mg kg(-1)) or usual care (neostigmine/glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular
blockade. Timing of reversal agent administration was based on the providers' clinical judgement. Primary endpoint was
the presence of residual neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio <0.9, using
TOF-Watch® SX. Key secondary endpoint was time between reversal agent administration and operating room discharge-
readiness; analysed with analysis of covariance.
 RESULTS:
 Of 154 patients randomized, 150 had a TOF value measured at PACU entry. Zero out of 74 sugammadex patients and 33
out of 76 (43.4%) usual care patients had TOF-Watch SX-assessed residual neuromuscular blockade at PACU admission
(odds ratio 0.0, 95% CI [0-0.06], P<0.0001). Of these 33 usual care patients, 2 also had clinical evidence of partial paralysis.
Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs
usual care (14.7 vs. 18.6 min respectively; P=0.02).
 CONCLUSIONS:
 After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened
the time from start of study medication administration to the time the patient was ready for discharge from the operating
room.

2015 May 10.
Postoperative Residual Neuromuscular Paralysis at an Australian
Tertiary Children's Hospital.
Ledowski T1, O'Dea , Meyerkort L2, Hegarty M3, von Ungern-Sternberg
BS4
 .
 Purpose. Residual neuromuscular blockade (RNMB) is known to be a significant
but frequently overlooked complication after the use of neuromuscular blocking
agents (NMBA). Aim of this prospective audit was to investigate the incidence
and severity of RNMB at our Australian tertiary pediatric center. Methods. All
children receiving NMBA during anesthesia were included over a 5-week period
at the end of 2011 (Mondays to Fridays; 8 a.m.-6 p.m.). At the end of surgery,
directly prior to tracheal extubation, the train-of-four (TOF) ratio was assessed
quantitatively. Data related to patient postoperative outcome was collected in
the postoperative acute care unit. Results. Data of 64 patients were analyzed.
Neostigmine was given in 34 cases and sugammadex in 1 patient. The incidence
of RNMB was 28.1% overall (without reversal: 19.4%; after neostigmine: 37.5%;
n.s.). Severe RNMB (TOF ratio < 0.7) was found in 6.5% after both no reversal
and neostigmine, respectively. Complications in the postoperative acute care
unit were infrequent, with no differences between reversal and no reversal
groups. Conclusions. In this audit, RNMB was frequently observed, particularly
in cases where patients were reversed with neostigmine. These findings
underline the well-known problems associated with the use of NMBA that are not
fully reversed.

insomma a farla breve...
Dal 2007 non è cambiato
molto nella incidenza della
PORC !!!
9 anni!!!!

MA CHE COSA CI IMPORTA
DELLA PORC?
Napoli SIA 2013

POPC after pancuronium and
atracurium(Pedersen AAS 1992;36;312-18)
0
2
4
6
8
10
12
%
POPC
panc
atrac
1559
1057

Viby Mogensen et al,AAS 1997
• 693 paz.randomizzati,cieco
• chir elettiva
• monitoraggio periop con Myotest e Tof
• confronto fra 1-5-2 ED95 di
atrac,vecu,panc.
• Antagonismo se necessario;
• estubaz a tof eguale, tattile e resp adeguata.

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
panc
atrac
vecu

Postoperative pulmonary
complications
0
5
10
15
20
%
popc popc con
blocco
residuo
popc senza
blocco
residuo
panc
vecu
atrac
panc
vecu
atrac

Napoli SIA 2013
0
5
10
15
20
%
popc popc con
blocco
residuo
popc senza
blocco
residuo
panc
vecu
atrac
panc
vecu
atrac

Popc secondo il tipo di
chirurgia
0
2
4
6
8
10
12
14
16
%
popc
addom
ortop
ginecol

Fattori di rischio per POPC nello
studio AAS.1997Residual neuromuscular block is a risk factor for postoperative
pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after
atracurium, vecuronium and pancuronium.
Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J, Skovgaard LT, Krintel JJ.
Acta Anaesthesiol Scand. 1997 Oct;41(9):1095-1103
 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

Murphy GS1, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS .Residual neuromuscular
blockade and critical respiratory events in the postanesthesia care unit.
Anesth Analg. 2008 Jul;107(1):130-7.)
 PACU admission first 15 min
 7459 patients :61 cases with critical respiratory
events(0.8%) ,hypoxemia 22/42,52.4% and
upper airway obstruction 15/42,35.7%
 Cases matched with control for age,sex,surgery
 Mean tof of critical cases 0.62+-0.20 vs 0.98+-0.07
 In conclusion, we observed evidence of incomplete
neuromuscular recovery in the majority of patients with
CREs in the PACU. Our findings suggest that the
residual effects of NMBDs can contribute to adverse
respiratory events after general anesthesia.

IL MONITOTRAGGIO INTRAOP
DELLA MIORISOLUZIONE RIDUCE
LA PORC??

Siiiiii..
 Murphy GS, Szokol JW, Marymont JH, et al.
Intraoperative acceleromyographic monitoring
reduces the risk of residual neuromuscular
blockade and adverse respiratory events in the
postanesthesia care unit. Anesthesiology 2008;
109:389–398.
 Murphy GS, Szokol JW, Avram MJ, et al.
Intraoperative acceleromyography monitoring
reduces symptoms of muscle weakness and
improves quality of recovery in the early
postoperative period. Anesthesiology 2011;
115:946–954.

Intraoperative acceleromyography monitoring reduces
symptoms of muscle weakness and improves quality of
recovery in the early postoperative period
Monitoraggio AMG quantit. vs
qualitativo
Riduce i TOFR<0.90
Riduce gli episodi di ipossiemia e
la loro durata nel trasporto dalla
sala op alla PACU e nella Pacu
Riduce gli interventi sulle vie aereeNapoli SIA 2013

Murphy GS1, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS, Nisman M.
Intraoperative acceleromyographic monitoring reduces the risk of residual neuromuscular
blockade and adverse respiratory events in the postanesthesia care unit.Anesthesiology. 2008
Sep;109(3):389-98.
 185 patients were randomized to intraoperative acceleromyographic monitoring
(acceleromyography group) or qualitative TOF monitoring (TOF group).
 Anesthetic management was standardized. TOF patients were extubated when standard
criteria were met and no fade was observed during TOF stimulation.
 A lower frequency of residual neuromuscular blockade in the PACU (TOF ratio < or = 0.9)
was observed in the acceleromyography group (4.5%) compared with the conventional
TOF group (30.0%; P < 0.0001).
 During transport to the PACU, fewer acceleromyography patients developed arterial
oxygen saturation values, measured by pulse oximetry, of less than 90% (0%) or airway
obstruction (0%) compared with TOF patients (21.1% and 11.1%, respectively; P < 0.002).
 The incidence, severity, and duration of hypoxemic events during the first 30 min of
PACU admission were less in the acceleromyography group (all P < 0.0001).
 CONCLUSIONS:
 Incomplete neuromuscular recovery can be minimized with acceleromyographic
monitoring. The risk of adverse respiratory events during early recovery from anesthesia
can be reduced by intraoperative acceleromyography use
Napoli SIA 2013

Napoli SIA 2013
Murphy GS1, Szokol
JW, Marymont JH,
Greenberg SB, Avram
MJ, Vender JS, Nisman
M.
Intraoperative
acceleromyographic
monitoring reduces
the risk of residual
neuromuscular
blockade and adverse
respiratory events in
the postanesthesia
care
unit.Anesthesiology.
2008 Sep;109(3):389-98.

Murphy GS1, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS, Nisman M.
Intraoperative acceleromyographic monitoring reduces the risk of residual
neuromuscular blockade and adverse respiratory events in the postanesthesia care
unit.Anesthesiology. 2008 Sep;109(3):389-98.
Napoli SIA 2013

Murphy GS1, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender
JS, Nisman M.
Intraoperative acceleromyographic monitoring reduces the risk of
residual neuromuscular blockade and adverse respiratory events in the
postanesthesia care unit.Anesthesiology. 2008 Sep;109(3):389-98.
Napoli SIA 2013

Intraoperative acceleromyography monitoring reduces symptoms of muscle
weakness and improves quality of recovery in the early postoperative period
 The incidence of residual blockade (train-of-four ratios less
than 0.9) was reduced in the acceleromyography group
(14.5% vs. 50.0% control group, with the 99% confidence
interval for this 35.5% difference being 16.4-52.6%, P <
0.0001).
 Generalized linear models revealed the acceleromyography
group had less overall weakness (graded on a 0-10 scale)
and fewer symptoms of muscle weakness across all time
points (P < 0.0001 for both analyses), but the number of signs
of muscle weakness was small from the time of arrival in the
PACU and did not differ between the groups at any time.

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 managementDella Rocca G, Iannuccelli
F, Pompei L, Pietropaoli P, Reale C, Di Marco P
 4.4%
» Batistaki C1, Tentes P, Deligiannidi P, Karakosta A, Florou P,
Kostopanagiotou G Residual neuromuscular blockade in a real life clinical
setting. Correlation with sugammadex or neostigmine administration.Minerva
Anestesiol.2016 82:550-8
Napoli SIA 2013

Conclusions
 Fino a che la funzione nm non viene
monitorizzata in maniera quantitativa
continua durante
intervento(MMG.AMG;ecc) la PORC
continuerà ad esistere e a dare un
contributo alle complicanze postop.
Napoli SIA 2013

Qualitative monitoring
Dose not differentiate
between 0.40-0.90 TOF!!!!
Mogensen et al. Tactile and
visual evaluation of response to
train-of-four nerve stimulation.
Anesthesiology 1985; 63:440-3.

Massimo ottenibile con DBS e tetano 100 Hz
metodiche più sofisticate come il DBS (double burst
stimulation)possono solo escludere,in assenza di fade,che
il TOF sia < 0.60
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.
 La valutazione visiva con tetano a 100 Hz è più sensibile
poiché la assenza di esaurimento visivo a 100 HZ è in genere
compatibile con una TOFR di circa 0.85 ,
 Baurain et al.Visual Evaluation of Residual Curarization in
Anesthetized Patients Using One Hundred-Hertz, Five-SecoBand Tetanic
Stimulation at the Adductor Pollicis Muscle .Anesth Analg 1998; 87:185–9
 Quindi,concludendo,dobbiamo assolutamente
ottenere TOF di almeno 0.90.

REVERSAL CON ANTI-
CHE....ANTICHE

Perchè la neostigmina non è
l’antagonista ideale
 Lentezza di azione
 Effetti collaterali;aritmie cardiache
 necessità di atropina o glicopirrolato per
neutralizzare gli effetti muscrainici
 Seguire le linee guida:
» Brull SJ, Murphy GS. Residual neuromuscular
block: Lessons unlearned. Part II: Methods to
reduce the risk of residual weakness. Anesth
Analg. 2010;111:129–40

Time from neostigmine
administration to TOFR 0.70
0.00
5.00
10.00
15.00
20.00
25.00
I twitch II twitch III twitch IV twitch
low max
min mediana
Napoli SIA 2013

Time from neostigmine administration
to TOFR 0.80
0
10
20
30
40
50
60
70
80
low
max
min
mediana
Napoli SIA 2013

Time from neostigmine administration
to TOFR 0.90
0
10
20
30
40
50
60
70
80
low
max
min
mediana
Napoli SIA 2013

Linee guida per neostigmina
 Dose massima efficace:s 60–80 μg/kg (per edrophonium,
1.0–1.5 mg/kg.[
 Non somministrare altro AntiChe se si raggiunta la dose
massima
 Preferire glicopirrolato in presenza di aritmie
 Iniettare lentamente
 Con monitoraggio quantitativo del blocco nm:
» Se tof 2 o > 0.9 non somministrare
» Se tof 2;aspettare una ripresa superiore
» Se TF è 4 e non si percepisce fade(tof 0.4-0.9) somministrare
la dose minima di 20 microgr/kg,specie se in presenza di
farmaci che aumentano il blocco(alogenati....)

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

Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile guided
reversal from cisatracurium induced neuromuscular
block.Anesthesiology 2002;96:45-50
 Anest with fent/prop/N2O
 cisatrac 0.15 mg/kg
 neostigmine 0.07 mg/kg administered at
reappearance of I,II,III,IV of TOF;tactile
vs Meccanomyography contralateral.
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.
Napoli SIA 2013

Fin qui ,fisiologia,mettere in
ordine slides Poi sulla collassabilità Eikermann M, Vogt FM, 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)
 Herbstreit F, Peters J, Eikermann M. Impaired upper airway integrity by residual neuromuscular blockade:
increased airway collapsibility and blunted genioglossus muscle activity in response to negative pharyngeal
pressure.
Anesthesiology. 2009 Jun;110(6):1253-60)
 (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
 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
 Sundrnan,H anne Witt, Rolf Olsson, Olle Ekberg, S,Richard Kuylenstierna, Lars I. Eriksson The Incidence and
Mechanisms of pharyngeal and Upper Esophageal Dysfunction in Partially Paralyzed
humans.Eva.Anesthesiology 2000;92:977-84
 Mirzakhani H, Williams J-N, Mello J, et al. Muscle weakness
 predicts pharyngeal dysfunction and symptomatic aspiration in
 long-term ventilated patients. Anesthesiology. 2013;119(2):
 389–397. )

Chemorecet perif
Chemrecett.centr SNC
Ipossia
ipercapnia iperventilazione

Corpi carotidei
Sito nicotinico
Sito
muscari
nico
nmb
atropina
ipossia

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

Le cause delle complicanze respiratorie
 possono essere attribuite a diversi fattori:
» alterazione della risposta ventilatoria alla ipossia
» disturbo della funzione dei muscoli respiratori
» diminuita capacità di proteggere le vie respiratorie dalla
inalazione di materiale gastrico

MA CHE COSA SUCCEDE
VERAMENTE QUANDO IL TOF
<0.90???

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

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

Eikermann M, Groeben H, Hüsing J, Peters Predictive value of mechanomyography and
accelerometry for pulmonary function in partially paralyzed volunteers.
JActa Anaesthesiol Scand. 2004 Mar;48(3):365-70.
 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

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

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

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.
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)
Napoli SIA 2013
.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.

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.
Napoli SIA 2013
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.

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

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.
Napoli SIA 2013
During 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.

Genioglossus function
Napoli SIA 2013

.( Herbstreit F1, Zigrahn D, Ochterbeck C, Peters J, Eikermann M.Neostigmine/glycopyrrolate
administered after recovery from neuromuscular block increases upper airway collapsibility by
decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiology.
2010 Dec;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.
 RESULTS:
 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

Genioglossus muscle activity as a function of negative mask pressure :percentage of
maximal activity when volunteer pressed his tongue against his teeth ,mouth
closed,with max.force

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.,airway
integrity is impaired
Napoli SIA 2013

.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

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

Sundrnan,H anne Witt, Rolf Olsson, Olle Ekberg, S,Richard Kuylenstierna, Lars I.
Eriksson The Incidence and Mechanisms of pharyngeal and Upper Esophageal
Dysfunction in Partially Paralyzed humans.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

Herbstreit F, Peters J, Eikermann M. Impaired upper airway integrity by residual neuromuscular
blockade: increased airway collapsibility and blunted genioglossus muscle activity in response to
negative pharyngeal pressure.
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

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

Sauer M, Stahn A, Soltesz S, Noeldge-Schomburg G, Mencke T The influence of residual
neuromuscular block on the incidence of critical respiratory events. A randomised,
prospective, placebo-controlled trial.. Eur J Anaesthesiol. 2011,128(12):842-8.)
 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

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.
 Questi risultati trovano conferma anche in studi morfologico
funzionali eseguiti sotto RMN lEikermann 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 )e
hanno rilevanza nei pazienti affetti da OSA ,suggerendo che il palato
molle gioca un ruolo di mediatore importante nel meccanismo di
dilatazione/restringimento durante la paralisi dei muscoli delle vie aeree
e il sonno.
Napoli SIA 2013

Grosse-Sundrup M1, Henneman JP, Sandberg WS, Bateman BT, Uribe JV, Nguyen NT,
Ehrenfeld JM, Martinez EA, Kurth T, Eikerman .Intermediate acting non-
depolarizing neuromuscular blocking agents and risk of postoperative
respiratory complications: prospective propensity score matched cohort
study. BMJ. 2012 Oct 15;345
.Prospective, propensity score matched cohort study.
 SETTING:
 General teaching hospital in Boston, Massachusetts, United States, 2006-10.
 46899 ptients,57068 procedures
18,579 surgical patients who received intermediate acting neuromuscular blocking agents during surgery
were matched by propensity score to 18,579 reference patients who did not receive such agents.
 MAIN OUTCOME MEASURES:
 The main outcome measures were oxygen desaturation after extubation (hemoglobin oxygen saturation
<90% with a decrease in oxygen saturation after extubation of >3%) and reintubations requiring
unplanned admission to an intensive care unit within seven days of surgery. We also evaluated effects
on these outcome variables of qualitative monitoring of neuromuscular transmission (train-of-four ratio)
and reversal of neuromuscular blockade with neostigmine to prevent residual postoperative
neuromuscular blockade.
 RESULTS:
 The use of intermediate acting neuromuscular blocking agents was associated with an increased risk of
postoperative desaturation less than 90% after extubation (odds ratio 1.36, 95% confidence interval 1.23 to 1.51)
and reintubation requiring unplanned admission to an intensive care unit (1.40, 1.09 to 1.80). Qualitative
monitoring of neuromuscular transmission did not decrease this risk and neostigmine reversal increased the
risk of postoperative desaturation less than 90% (1.32, 1.20 to 1.46) and reintubation (1.76, 1.38 to 2.26).
 CONCLUSION:
 The use of intermediate acting neuromuscular blocking agents during anesthesia was associated with an increased risk of clinically meaningful respiratory complications. Our data suggest that the strategies
used in our trial to prevent residual postoperative neuromuscular blockade should be revisited.
 Comment in
 Antagonising neuromuscular block at the end of surgery. [BMJ. 2012

(Grosse-Sundrup M1, Henneman JP, Sandberg WS, Bateman BT, Uribe JV, Nguyen NT,
Ehrenfeld JM, Martinez EA, Kurth T, Eikerman .Intermediate acting non-depolarizing
neuromuscular blocking agents and risk of postoperative respiratory complications:
prospective propensity score matched cohort study. BMJ. 2012 Oct 15;345
No nmb/si nmb No neostigm/si neo NO Nmb monit /si
Desat <90
3.70 vs 4.9 3.8 vs 5.01 4.08 vs 4.82
Desat <80
0,6 vs 1.14 0.85 vs 0.99 0.868 vs 1.00
reintub
0,58 vs 0.81 0.52 vs 0.92 0.597 vs 0.88
Morte intraosp
0,25 vs 0,29 0.27 vs 0.28 0.27 vs 0.28
18,579 surgical patients who received intermediate acting neuromuscular
blocking agents during surgery were matched by propensity score to 18,579
reference patients who did not receive such agents.

(Grosse-Sundrup M1, Henneman JP, Sandberg WS, Bateman BT, Uribe JV, Nguyen NT, Ehrenfeld JM,
Martinez EA, Kurth T, Eikerman .Intermediate acting non-depolarizing neuromuscular blocking agents
and risk of postoperative respiratory complications: prospective propensity score matched cohort study.
BMJ. 2012 Oct 15;345
 The study shows that the use of modern
intermediate acting non depolarizing
agents may put the patients at risk for
postop resp complications
 Reintubation after surgery increases
mortality and healthcare costs
 Mortality of postsurgical patients with
unplanned admission to ICU is high with
resp complications being the most
important problem..

RESIDUAL NEUROMUSCULAR
BLOCK AFFECTS PULMONARY
FUNCTION
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

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). 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 .
Napoli SIA 2013
TOFR 0.85-0.95 TOFR 0.65-0.75 TOFR ratio of

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.
0
2
4
6
8
10
12
inability to sustain
head lift >5 sec
iability to seal
mouthpiece
inability to swallow
normally
fade of contraction
visible
upper airway
obstruction
tof 0.5
tof 0.8
tof 1
Num
Napoli SIA 2013

Il blocco parziale (TOFR 0.5-0.80)
 Aumenta la collassabilità delle prime vie resp.con
riduzione del volume degli spazi retroglottici e
retropalatini(diminuzione del diametro)
 Diminuisce l’attività del musc.genioglosso
 Senza modificazione dei parametri resp
principali(TV,TLV:timing resp....)
 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
Napoli SIA 2013

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

The Incidence and Mechanisms of pharyngeal and Upper Esophageal
Dysfunction in Partially Paralyzed humansSundrnan,H anne Witt, Rolf Olsson, Olle
Ekberg, S,Richard Kuylenstierna, Lars I. Eriksson The Incidence and Mechanisms of pharyngeal
and Upper Esophageal Dysfunction in Partially Paralyzed humans.Anesthesiology 2000;92:977-84
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

MA CI SONO DELLE NUOVE
ACQUISIZIONI...........

LA NEOSTIGMINA PUÒ FARE
MALE
1)

Neostigmina dopo ripresa completa(...) e
aumento delle complicanze
 Collassabilità delle vie aeree sup
 Atelettasia
 Edema polmonare
 Frequenza di reintubazione
 Prolungamento della degenza nella
PACU

Sasaki N, Meyer MJ, Malviya SA, Stanislaus AB, MacDonald T, Doran
ME, et al. Effects of neostigmine reversal of nondepolarizing
neuromuscular blocking agents on postoperative respiratory outcomes: A
prospective study. Anesthesiology. 2014;121:959–68.
 3,000 patients, prospective, observer-blinded, observational study.
 We documented the intraoperative use of neuromuscular blocking agents and neostigmine. At
postanesthesia care unit admission, we measured train-of-four ratio and documented the ratio of peripheral
oxygen saturation to fraction of inspired oxygen (S/F). The primary outcome was oxygenation at
postanesthesia care unit admission (S/F). Secondary outcomes included the incidence of postoperative
atelectasis and postoperative hospital length of stay. Post hoc, we defined high-dose neostigmine as more
than 60 μg/kg and unwarranted use of neostigmine as neostigmine administration in the absence of
appropriate neuromuscular transmission monitoring.
 RESULTS:
 Neostigmine reversal did not improve peripheral O2 saturation /FiO2
 increased incidence of atelectasis (8.8% vs. 4.5%; odds ratio, 1.67 [1.07 to 2.59]).
 High-dose neostigmine was associated with longer time to postanesthesia care
unit discharge readiness (176 min [165 to 188] vs. 157 min [153 to 160]) and longer
postoperative hospital length of stay (2.9 days [2.7 to 3.2] vs. 2.8 days [2.8 to 2.9]).
 Unwarranted use of neostigmine (n = 492) was an independent predictor of
pulmonary edema (odds ratio, 1.91 [1.21 to 3.00]) and reintubation (odds ratio, 3.68
[1.10 to 12.4]).
 CONCLUSIONS:
 Neostigmine reversal did not affect oxygenation but was associated with increased atelectasis. High-dose
neostigmine or unwarranted use of neostigmine may translate to increased postoperative respiratory
morbidity

Incidence of postop atelectasis greater in pts
who received neostigmine
Sasaki N, Meyer MJ, Malviya SA, Stanislaus AB, MacDonald T, Doran ME, et al. Effects of neostigmine reversal
of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: A prospective
study. Anesthesiology. 2014;121:959–68

Pts who received unwarranted dose of
neostigmine had more complications
Sasaki N, Meyer MJ, Malviya SA, Stanislaus AB, MacDonald T, Doran ME, et al. Effects of
neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative
respiratory outcomes: A

BMJ. 2013; 346: 1460.
Neostigmine reversal doesn’t improve postoperative respiratory safety
Matthew J Meyer, Brian T Bateman, Tobias Kurth, Matthias Eikermann,
Neo no Neo si
Oxygen desaturation
<90%
4.43 4.98
Oxygen desaturation
<80%
0.101 0.110
Reintubation 0.78 0.87

PERCHÈ LA NEOSTIGMINA
FALLISCE??

La collassabilità delle vie aeree superiori dopo neostigmina era
già stata dimostrata in lavori su ratti negli anni precedenti....
 Anesthesiology. 2007 Oct;107(4):621-9.
Unwarranted administration of acetylcholinesterase
inhibitors can impair genioglossus and diaphragm
muscle function.
Eikermann M, Fassbender P, Malhotra A, Takahashi M,
Kubo S, Jordan AS, Gautam S, White DP, Chamberlin NL
 Br J Anaesth. 2008 Sep;101(3):344-9. Neostigmine but not
sugammadex impairs upper airway dilator muscle
activity and breathing.
Eikermann M, Zaremba S, Malhotra A, Jordan AS, Rosow C,
Chamberlin NL.

Volontari sani con neo/glicopirr
somministrati a ripresa del TOFr
 Aumenta la collassabilità (aumenta la press.critica
di chiusura,cioè è meno neg!!)in modo simile al
blocco parziale da nmb
 Diminuisce l’attività del musc genioglosso
– Herbstreit F, Peters J, Eikermann M. Impaired upper airway integrity by residual
neuromuscular blockade: increased airway collapsibility and blunted genioglossus
muscle activity in response to negative pharyngeal pressure.
Anesthesiology. 2009 Jun;110(6):1253-60
– Herbstreit F1, Zigrahn D, Ochterbeck C, Peters J, Eikermann
M.Neostigmine/glycopyrrolate administered after recovery from
neuromuscular block increases upper airway collapsibility by decreasing
genioglossus muscle activity in response to negative pharyngeal pressure.
Anesthesiology. 2010 Dec;113(6):1280-8)
Napoli SIA 2013

Bulka et al.Nondepolarizing blocking agents ,reversal and risk of postoperative
pneumonia.Anesthesiology 2016;125:647-655.
 I problemi respiratori da pazienti inadeguatamente
antagonizzati nella PACU dovrebbero essere ben noti
agli anestesisti ...
 8 anni di dati in un reparto universitario
 Ipotesi di lavoro:
» i paz. che hanno ricevuto miorilassanti durante intervento
hanno un rischio maggiore di polmonite rispetto a quelli
che non ne hanno ricevuti
» Inoltre i paz. che hanno ricevuto miorilass. ma non sono
stati antagonizzati presentano un rischio maggiore di
polmonite rispetto a quelli antagonizzati

Miorilassanti SI/NO e antagonismo
SI/NO e rischio di polmonite
Miorilass vs NO
miorilass:1455 paz
 MIOril:polmonite 38
 No Mioril :polmonite 22
 Probabilità di polmonite 73
% + dopo mioril
Antagonismo vs NO
antagonismo:1320 paz
 Antag:70 polmonite
 NO antag:149 con polmonite
 Probabilità 211 % maggiore di
polmonite senza antag.

Conclusioni
 Non antagonizzare la paralisi residua aumenta i
rischi per i pazienti;aspirazione,insuff resp,polmonite
 Senza contare che ci sono lavori che hanno
dimostrato come la mancata antagonizzazione sia
correlata agli eventi avversi.....
MA
 La neostigmina,oltre ai problemi farmacologici
noti.......Aumenta la collassabilità delle vie aeree
superiori e quindi può favorire le complicanze
respiratorie!!

Aumento dei costi delle Ko
resp
 Dimick JB, Chen SL, Taheri PA, Henderson WG,
Khuri SF,Campbell DA. Hospital costs associated
with surgical complications: a report from the
private-sector National Surgical Quality
Improvement Program. J Am Coll Surg.
2004;199(4): 531–7.)
 Ramachandran SK, Nafiu OO, Ghaferi A, Tremper
KK, Shanks A, Kheterpal S. Independent predictors
and outcomes of unanticipated early postoperative
tracheal intubation after nonemergent,noncardiac
surgery. Anesthesiology. 2011;115(1):44–53.)
 Fin qui??? Tempo???

Fin qui
 Curr Anesthesiol Rep. 2014 Dec;4(4):290-302.
 Residual Paralysis: Does it Influence Outcome After Ambulatory Surgery?
 Farhan H1, Moreno-Duarte I1, McLean D1, Eikermann M1.
 Author information
 1Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical
School, Massachusetts General Hospital, 55, Fruit Street, Boston, MA 02115, USA.
 Abstract
 Neuromuscular blocking agents are used to facilitate tracheal intubation in patients undergoing
ambulatory surgery. The use of high-dose neuromuscular blocking agents to achieve muscle
paralysis throughout the case carries an increased risk of residual post-operative neuromuscular
blockade, which is associated with increased respiratory morbidity. Visually monitoring the train-of-
four (TOF) fade is not sensitive enough to detect a TOF fade between 0.4 and 0.9. A ratio <0.9
indicates inadequate recovery. Quantitative neuromuscular transmission monitoring (e.g.,
acceleromyography) should be used to exclude residual neuromuscular blockade at the end of the
case. Residual neuromuscular blockade needs to be reversed with neostigmine, but it's use must
be guided by TOF monitoring results since deep block cannot be reversed, and neostigmine
administration after complete recovery of the TOF-ratio can induce muscle weakness. The
development and use of new selectively binding reversal agents (sugammadex and calabadion)
warrants reevaluation of this area of clinical practice.

Sugammadex incapsulating
rocuronium

CONFRONTI NEOSTIGMINA VS
SUGAMMADEX:PER FORTUNA ESISTE UNA
REVIEW.....

TOFr recovery 0.9 after sugammadex vs
neostigmine

Time to recovery after
sugammadex 16 mg/kg

Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007362.
Sugammadex, a selective reversal medication for preventing
postoperative residual neuromuscular blockade.Abrishami A1, Ho J,
Wong J, Yin L, Chung F.
 The results suggest that, compared with
placebo or neostigmine, sugammadex can
more rapidly reverse rocuronium-induced
neuromuscular blockade regardless of the
depth of the block. We identified 2, 4, and 16
mg/kg of sugammadex for reversal of
rocuronium-induced neuromuscular blockade at
T(2) reappearance , 1 to 2 post-tetanic counts,
and 3 to 5 minutes after rocuronium,
respectively.

Review del PONV dopo
sugammadex vs neostigmine

Review della paralisi residua
sugammadex vs neostigmine

Review dei segni minori di debolezza
muscolare sugammadex vs neostigmine

Review del rischio relativo di
reintubazione sugammadex vs
neostigmine

collaterali di sugammadex vs
neostigmine

Abad-Gurumeta A, Ripollés-Melchor J, Casans-Francés R, Espinosa A, Martínez-
Hurtado E, Fernández-Pérez C, Ramírez JM, López-Timoneda F, Calvo-Vecino JM;
Evidence Anaesthesia Review Group doi: 10.1111/anae.13277.
A systematic review of sugammadex vs neostigmine for reversal of neuromuscular
blockade.) (Anaesthesia. 2015 Dec;70(12):1441-52.
.
. 17 randomised controlled trials with 1553 participants.
 Sugammadex reduced all signs of residual
postoperative paralysis, relative risk (95% CI) 0.46 (0.29-0.71), p
= 0.0004
 and minor respiratory events, relative risk (95% CI) 0.51 (0.32-
0.80), p = 0.0034.
 There was no difference in critical respiratory events, relative risk (95%
CI) 0.13 (0.02-1.06), p = 0.06.
 Sugammadex reduced drug-related side-effects, relative risk (95% CI)
0.72 (0.54-0.95), p = 0.02.
 There was no difference in the rate of postoperative nausea or the rate of
postoperative vomiting, relative risk (95% CI) 0.94 (0.79-1.13), p = 0.53,
and 0.87 (0.65-1.17), p = 0.36 respectively.


Mirzakhani H, Williams J-N, Mello J, et al. Muscle weakness
predicts pharyngeal dysfunction and symptomatic aspiration in
long-term ventilated patients. Anesthesiology. 2013;119(2):
389–397.
 Fin qui

ANCHE IL SUGAMMADEX NON
BASTA........
3

Martinez-Ubieto J1, Ortega-Lucea S, Pascual-Bellosta A, Arazo-Iglesias I,
Gil-Bona J, Jimenez-Bernardó T, Muñoz-Rodriguez Prospective study of
residual neuromuscular block and postoperative respiratory
complications in patients reverted with neostigmine versus
sugammadex.Minerva Anestesiol. 2015 Oct 16.
0
5
10
15
20
25
30
35
40
cisatra cisatr+neo rocu rocu+sugamma
558 pts,Pacu
1.2%
%P
O
R
C

Critical respiratory events
critical resp events,minimalCREserious
cisatr 27.5 8.7
cisatr+neo 17.5 7.2
rocu 10.5 9.7
rocu+sugamma2.3 1
Minor:
- Upper airway obstruction requiring intervention
- Hypoxemia with SpO2<94% *
- Major in the PACU:
- Need for reintubation of the patient
- Major, late.atelectasis,pneumonia

Batistaki C1, Tentes P, Deligiannidi P, Karakosta A, Florou P,
Kostopanagiotou G Residual neuromuscular blockade in a real life
clinical setting. Correlation with sugammadex or neostigmine
administration.
Minerva Anestesiol.(2016 82:550-8.
 Overall prevalence of RNMB 10.8% (Rocu 12.7%,Cis 6.25)
 a worrisome observation revealed was the relatively
low percentage (4.4%) of intraoperative
neuromuscular monitoring, according to previous studies, the
absence of routine monitoring increases the risk of rnMB, but also
reflects reality due to unavailability of monitoring devices in all operating
theaters and lack of appropriate education on this is- sue.4, 29
 most of the times anesthesiologists preferred to
reverse neuromuscular blockade based only on
clinical signs.
 as stated in the multicenter study by Kotake et al.,30 even with
sugammadex, an incidence of rnMB as high as 9.4% was observed
when neuromuscular monitoring was no used.

L’uso del sugammadex non
esime dal monitoraggio nm
 Vannucci a. sugammadex can be part of the
solution. let’s not make it part of the problem!
Minerva anestesiol 2013;79:587-9.
 Della rocca g, Di Marco P, Beretta l, De
gauidio ar, ori c, Mastronardi P. Do we need
sugammadex at the end of a general
anesthesia to reverse the action of neuromus-
cular blocking agents? Position Paper on
sugammadex use. Minerva anestesiol
2013;79:661-6.

Kotake et al (Kotake Y, Ochiai R, Suzuki T, Ogawa S, Takagi S, Ozaki M, et al. Reversal with
sugammadex in the absence of monitoring did not preclude residual neuromuscular blockade.
Anesth Analg 2013;117:345-5
 1)Sugammadex decreased the incidence of
postoperative residual weakness compared with
neostigmine (4.3% vs 23.9% for TOFR <0.9 and
46.2% vs 67.0% for TOFR <1.0).
 2)the risk of TOFR <0.9 after tracheal extubation after
sugammadex remains as high as 9.4% in a clinical
setting in which neuromuscular monitoring (objective
or subjective) was not used.
 Our finding underscores the importance of
neuromuscular monitoring even when sugammadex is
used for antagonism of rocuronium-induced
neuromuscular block.

Derivati del sugammadex
 Randomly substituted CD derivatives (CMGCD and SBGCD) can
potentially reverse the neuromuscular blockade similarlyto
Sugammadex
 Preparation of randomly substituted CD derivatives is more cost-
effective than that of Sugammadex
 Minute changes in the CD structure can have huge impact on the
affinity towards NMBAs thus understanding the interactionmechanism
are essential.
Napoli SIA 2013

NUOVI MIORILASSANTI E
NUOVE ACQUISIZIONI

 Future Med Chem. 2013 Nov;5(17):2075-89. doi: 10.4155/fmc.13.164.
 Cucurbit[n]uril type hosts for the reversal of steroidal neuromuscular blocking
agents.
 Macartney DH1.
 Abstract
 The ideal neuromuscular blocking agent (NMBA) is regarded as being a non-
depolarizing equivalent of succinylcholine, having a rapid onset and short duration of
action, with minimal side effects. In the absence of a single drug, the administration of
an aminosteroid NMBA, such as rocuronium, followed by reversal using an
acetylcholinesterase inhibitor, such as neostigmine, is commonly employed. A different
and safer approach to rapidly reversing the action of the NMBA, by encapsulating it
with a macrocyclic or acyclic host molecule, such as the cyclodextrin sugammadex or
more recently, cucurbituril-type hosts such as cyclic cucurbit[7]uril and the acyclic
glycoluril tetramer calabadion 1, is described.

Calabadion
 Molecola “contenitore” con una cavità
idrofobica
 Queste molecole hanno spiccata affinità
per i composti alkanici con ammonio

Struttura chimica del
calabadion

 Anesthesiology. 2013 Aug;119(2):317-25. doi: 10.1097/ALN.0b013e3182910213.
 Calabadion: A new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents.
 Hoffmann U1, Grosse-Sundrup M, Eikermann-Haerter K, Zaremba S, Ayata C, Zhang B, Ma D, Isaacs L, Eikermann M.
 Abstract
 INTRODUCTION:
 To evaluate whether calabadion 1, an acyclic member of the Cucurbit[n]uril family of molecular containers, reverses
benzylisoquinoline and steroidal neuromuscular-blocking agent effects.
 METHODS:
 A total of 60 rats were anesthetized, tracheotomized, and instrumented with IV and arterial catheters. Rocuronium (3.5 mg/kg) or
cisatracurium (0.6 mg/kg) was administered and neuromuscular transmission quantified by acceleromyography. Calabadion 1 at
30, 60, and 90 mg/kg (for rocuronium) or 90, 120, and 150 mg/kg (for cisatracurium), or neostigmine/glycopyrrolate at 0.06/0.012
mg/kg were administered at maximum twitch depression, and renal calabadion 1 elimination was determined by using a H NMR
assay. The authors also measured heart rate, arterial blood gas parameters, and arterial blood pressure.
 RESULTS:
 After the administration of rocuronium, resumption of spontaneous breathing and recovery of train-of-four ratio to 0.9 were
accelerated from 12.3 ± 1.1 and 16.2 ± 3.3 min with placebo to 4.6 ± 1.8 min with neostigmine/glycopyrrolate to 15 ± 8 and 84 ± 33
s with calabadion 1 (90 mg/kg), respectively. After the administration of cisatracurium, recovery of breathing and train-of-four ratio
of 0.9 were accelerated from 8.7 ± 2.8 and 9.9 ± 1.7 min with placebo to 2.8 ± 0.8 and 7.6 ± 2.1 min with
neostigmine/glycopyrrolate to 47 ± 13 and 87 ± 16 s with calabadion 1 (150 mg/kg), respectively. Calabadion 1 did not affect heart
rate, mean arterial blood pressure, pH, carbon dioxide pressure, and oxygen tension. More than 90% of the IV administered
calabadion 1 appeared in the urine within 1 h.
 CONCLUSION:
 Calabadion 1 is a new drug for rapid and complete reversal of the effects of steroidal and benzylisoquinoline neuromuscular-
blocking agents

Tempi di recupero TOF 0.90 con
calabadion 1
 rocuronium cisatracurium
 calabadion 1.2 1.2
 placebo 16 10
 neostigmina 4.5 7.6
 Il calabadion 2 ha affinità ancora maggiore !!!
 Assenza di effetti avversi o attività cardiovascolare.
» Anesthesiology. 2015 Dec;123(6):1337-49. Comparative Effectiveness of
Calabadion and Sugammadex to Reverse Non-depolarizing
Neuromuscular-blocking Agents.
» Haerter F1, Simons JC, Foerster U, Moreno Duarte I, Diaz-Gil D, Ganapati
S, Eikermann-Haerter K, Ayata C, Zhang B, Blobner M, Isaacs L, Eikermann
M.

Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-
depolarizing Neuromuscular-blocking Agents.
Haerter F1, Simons JC, Foerster U, Moreno Duarte I, Diaz-Gil D, Ganapati S, Eikermann-
Haerter K, Ayata C, Zhang B, Blobner M, Isaacs L, Eikermann M.
 The authors evaluated the comparative effectiveness of calabadion 2 to reverse non-depolarizing
neuromuscular-blocking agents (NMBAs) by binding and inactivation.
 METHODS:
 The dose-response relationship of drugs to reverse vecuronium-, rocuronium-, and cisatracurium-induced
neuromuscular block (NMB) was evaluated in vitro (competition binding assays and urine analysis), ex vivo (n =
34; phrenic nerve hemidiaphragm preparation), and in vivo (n = 108; quadriceps femoris muscle of the rat).
Cumulative dose-response curves of calabadions, neostigmine, or sugammadex were created ex vivo at a
steady-state deep NMB. In living rats, the authors studied the dose-response relationship of the test drugs to
reverse deep block under physiologic conditions, and they measured the amount of calabadion 2 excreted in the
urine.
 RESULTS:
 In vitro experiments showed that calabadion 2 binds rocuronium with 89 times the affinity of sugammadex (Ka =
3.4 × 10 M and Ka = 3.8 × 10 M-). The results of urine analysis (proton nuclear magnetic resonance),
competition binding assays, and ex vivo study obtained in the absence of metabolic deactivation are in
accordance with an 1:1 binding ratio of sugammadex and calabadion 2 toward rocuronium. In living rats,
calabadion 2 dose-dependently and rapidly reversed all NMBAs tested. The molar potency of calabadion 2 to
reverse vecuronium and rocuronium was higher compared with that of sugammadex. Calabadion 2 was
eliminated renally and did not affect blood pressure or heart rate.
 CONCLUSIONS:
 Calabadion 2 reverses NMB induced by benzylisoquinolines and steroidal NMBAs in rats more effectively, i.e.,
faster than sugammadex. Calabadion 2 is eliminated in the urine and well tolerated in rats

Ripresa degli sforzi respiratori dopo antagonismo del vecu con calabadion1 & 2
,sugammadex ,neostigmina,placebo

Ripresa del Tof 0.90 dopo antagonismo del vecu con calabadion1 & 2

Ripresa degli sforzi respiratori dopo antagonismo del rocu con
calabadion1 & 2 ,sugammadex ,neostigmina,placebo

Ripresa del Tof 0.90 dopo antagonismo del rocu con calabadion1 & 2

Ripresa degli sforzi respiratori dopo antagonismo del cisatra con calabadion
2,neostigmina,placebo

Ripresa del Tof 0.90 dopo antagonismo del cisatrac con calabadion
2,neostigmina,placebo

 Anesthesiology. 2016 Jun;124(6):1417.
doi: 10.1097/ALN.0000000000001097.
 Effectiveness versus Efficacy of
Calabadion and Sugammadex for
Nondepolarizing Neuromuscular
Blocking Agent Reversal.
 Lim G1, Landsittel DP.

 Expert Opin Pharmacother. 2016;17(6):819-33. doi: 10.1517/14656566.2016.1145667. Epub 2016 Mar 14.
 Reversing neuromuscular blockade: inhibitors of the acetylcholinesterase versus the encapsulating agents sugammadex
and calabadion.
 Haerter F1, Eikermann M1,2.
 Abstract
 INTRODUCTION:
 Acetylcholinesterase inhibitors (neostigmine, edrophonium) and encapsulating agents (sugammadex and calabadion) can be used
to reverse residual neuromuscular blockade (NMB).
 AREAS COVERED:
 This review provides information about efficacy, effectiveness, and side effects of drugs (acetylcholinesterase inhibitors and
encapsulating agents) used to reverse neuromuscular blocking agents (NMBAs).
 EXPERT OPINION:
 The therapeutic range of acetylcholinesterase-inhibitors is narrow and effectiveness studies demonstrate clinicians don't use these
unspecific reversal agents effectively to increase postoperative respiratory safety. The encapsulating drugs sugammadex and
calabadion reverse all levels of NMB, and complete recovery of muscle strength can be achieved almost immediately after
administration. For this reason encapsulating agents can be used as a solution for "cannot intubate cannot ventilate"- situations.
Poor binding selectivity of encapsulating agents carries the risk of displacement of the NMBA by a competitively binding drug,
which may lead to recurarization. In order to avoid side-effects, related to unspecific binding of endogenous proteins and drugs
administered perioperatively it is prudent to titrate the dose of reversal agents to the minimal effective dose, depending on the
depth of neuromuscular transmission block identified by neuromuscular transmission monitoring. Calabadions provide a diversified
(increased binding selectivity) and expanded (reversal of benzylisoquinolines) spectrum of possible indications

Nora e reversal colorato slideshare; NaPoli i SIA 2016

Nora e reversal colorato slideshare; NaPoli i SIA 2016

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