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Chondodendron tomentosum
(fam. Menispermaceae).
D- tubocurarina (Intracostin)
Rationale of NMBAs
Adjuvant for tracheal intubation
NMB-induced relaxation
Improved visualization of vocal
cords
Limited resistance to the
laryngoscope
Decreased frequency of vocal
cord inflammation, laryngeal
hematomas, and postoperative
hoarseness
a Patients
Rapid onset
Rapid recovery
Dose-dependent duration
No side-effects
Elimination independent of organ function
No active or toxic metabolites
Reversible
1942
1949
1951
1960
1964
1980
1980
1992
1994
1995
INTOCOSTRIN
d-TUBOCURARINA
SUCCINILCOLINA
PANCURONIO
ALCURONIO
ATRACURIO
VECURONIO
MIVACURIO
ROCURONIO
CISATRACURIO
Muscle Relaxants
Definition
Muscle relaxants are agents that interfere with ACh action
Depending on their effects they are classified in
AGONISTS (depolarizing)
ANTAGONISTS or COMPETITIVES (non depolarizing)
D-Tubocurarine
Succinylcholine
1951
1942
Aminosteroids
Pancuronium
Vecuronium
1967
Rocuronium
1980
1990
Benzylisoquinolines
Atracurium - Cis.Atracurium
1980
1995
Mivacurium
1988
STRUTTURA CHIMICA
Composti dellammonio quaternario (succinilcolina)
Aminosteroidi ( pancuronio, vecuronio, mivacurio,
rocuronio, rapacuronio)
Derivati benzilisochinolinici ( atracurio, cis-atracurio)
DURATA DAZIONE
Breve, media , lunga
Muscle Relaxants
Dose-Effect
Ed 95: effective dose (mg/kg) to block 95% of receptors
0,05
Cis Atracurium
0,05
Pancuronium
0,06
Mivacurium
0,08
Succinylcholine
0,15 - 0,3
Atracurium
0,25
Rocuronium
0,3
Succinylcholine chloride
Short:
Mivacurium chloride
Classification of Neuromuscular
Blockers by Duration of Action (Minutes)
UltraShort
Short
Intermediate
Long
Clinical duration
(injection to T25)
6-8
12 - 20
30 - 45
>60
Recovery time
(injection to T95)
<15
25 - 30
50 - 70
90 -180
Recovery index
(T25 to T75)
2-3
10 -15
>30
Examples
succinylcholine 1
mivacurium
Cis-atracurium
doxacurium
NMBAs
Summary
Time to
Intubation
(min)
Clinical
Duration
(min)
30/09/2015
Roc
Vec
Panc
Atra
1.5-2
1.5-2.5 1.5-2
30-40
20-30
86-100 15-40
Cis
Miv
1.5-2.5 0.5-1
55
20-25
Sux
+8
16
Economic Evaluation of
Anesthesia
The Cost of Intubation
Succinylcholine
100 mg
$1
Atracurium
100 mg
$ 33.50
Mivacurium
20 mg
$ 20.90
Pancuronium
5 mg
$ 6.80
Vecuronium
10 mg
$ 16.0
Rocuronium
50 mg
$ 12.75
Cisatracurium
20 mg
$ 19.95
Muscle Relaxants
Depolarizing
Succinylcholine is rapidly hydrolized by plasma cholinesterase (not by
acetylcholinesterase)
Multiple Actions:
1) Depolarizes muscular membrane
2) Inactivates Na+ channels (perijunctionale)
3) Inhibits normal cycle of Na+ channels (remaining membrane)
Succinylcholine
Side Effects (1)
Myalgia (72% Can J Anesth 2000 (47) 5:
427-432)
Fasciculations (about 30-50%)
Malignant Hypothermia
Hyperpotassimia
Increased IOP and ICP
Vagal effects
Succinylcholine
Side Effects (2)
Anaphylaxis
Prolonged block
Masseter spasm
Neuromuscular diseases
Cardiac Arrest
Wide range of Contradictions
CONTRAINDICATIONS OF SUCCINYLCHOLINE
Burns
Sepsis
Severe trauma
Acidosis
Muscular diseases (muscular dystrophy)
Upper neuron lesions and peripheral denervation
Hyper/hypokaliemia
Eye trauma
Prolonged immobility
Atypical cholinesterase
...Succinylcholine controversy
Burroughs Wellcome applied to the FDA for a
change in the package insert to limit the use
of SCh in children
After receiving evidence from the profession,
FDA recommended that use of SCh in children
be reserved for emergency intubation or
instances where immediate securing of the
airway is necessary.
Succinylcholine
Because succinylcholine is more hazardous
than any other relaxants, the risk involved in its
use must be counterbalanced by a benefit to
the patient(Feldman, 1996)
In spite of all its disavantages, it has unique
properties: it produces a rapid, profound,
short-lived relaxation (Lee, Baillieres Clinical
Anaesthesiology, 1994)
Neuromuscular Blockers:
Chemical Structure & Key Characteristics
Aminosteroids
Vagolytic
Partially block cardiac muscarinic receptors involved in
heart rate slowing, resulting in increased heart rate:
rapacuronium > pancuronium > rocuronium >
vecuronium
Generally do not promote histamine release
Exception: rapacuronium
Organ-dependent elimination
Kidneys and liver
Neuromuscular Blockers:
Chemical Structure & Key Characteristics
Benzylisoquinolines
Absence of vagolytic effect
these drugs do not block cardiac-vagal (muscarinic)
receptors
Histamine release
dTc > atracurium > mivacurium > cisatracurium
can cause rare bronchospasm, decreased blood
pressure, increase of heart rate
Generally organ-independent elimination1
esp: atracurium, cisatracurium, mivacurium
Noncumulative2
1Stenlake
2Ali
5. DIAFRAMMA
4. ADDUTTORE POLLICE
3. ORBICULARIS OCULI
2.MUSCOLI
INTRINSECI
LARINGE: corde
vocali
INTERMEDIATE
ACTING
Rocuronium
Structurally similar to vecuronium
Introduced in clinical practice in 1994
First non-depolarizing to compete with
succinylcholine for rapid sequence intubation
(rapid onset)
Rocuronium
Rapid Onset
Intermediate duration
Reversible
Stable hemodynamics
No histamine release
No active metabolites
Rocuronium
Pharmacokinetics
Plasma elimination by hepatic uptake and
elimination
No active metabolites
Reduced volume of distribution (Vd) compared
to vecuronium
ROCURONIUM BROMIDE:
CARDIOVASCULAR PROFILE
Favorable cardiovascular profile
Histamine release unlikely
100
90
80
70
60
50
40
3.0
0.0 1.0 2.0
4.05.0
Time (minutes)
6.0
100
90
80
70
60
50
0.0 1.0 2.0 3.0 4.0 5.0 6.0
Time (minutes)
600 mcg/kg
900 mcg/kg
1200 mcg/kg
2.0
1.5
1.0
0.5
0.0
0.0
5.0
1,2 mg/kg
1h e 15 min
30/09/2015
37
Cis-atracurium
One of the 10 stereoisomers of
atracurium
No histamine release
Cis-atracurium
Pharmacokinetics
Metabolized by Hofmann reaction
Metabolites: laudanosine
More potent so less molecules thus less
laudanosine
Cis-atracurium
Pharmacodynamics
Histamine release starting from 5 x
ED95
Clinically relevant from 8 x ED95
No cumulative effects
Cis-Atracurium
Slow Onset
Intermediate duration
Reversal is possible
Stable cardiovascular
No histamine release
Non active metabolites (less laudanosine)
Neuromuscular Monitoring
Neuromuscular Monitoring
WHY ?
When to intubate
When to extubate
When to use it
Should be used whenever utilizing NMBAs
Particulary indicated:
LONG SURGICAL PROCEDURES
.
PATIENTS IN
DISEASES)
WHICH
BLOCKADE
DRUG INTERCATIONS
MAY
BE
PROLONGED
(NEUROM.
Muscle Relaxants
Dose-Effect
100
50
Recovery Index
Onset Time
0
Time
30/09/2015
Somministrazione
miscela (neostigm+
atropina)
47
Neuromuscular Monitoring
in clinical practice
Extubation
Intubation
NMBA bolus
NMBA bolus
Anticohlinesterase
Neuromuscular Monitoring
Mechanomyography
Neuromuscular Monitoring
Electromyography
Neuromuscular Monitoring
Acceleromyography
Neuromuscular Monitoring
Principle of Acceleromyography
Newtons Law of Acceleration
Neuromuscular Monitoring
In clincal practice
Acceleromyographic
transducer
Stimulation
electrodes
Neuromuscular Monitoring
Electrodes position
Neuromuscular Monitoring
Electrodes Cable
Acceleration transducer cable
Conseguenze cliniche
della curarizzazione residua
recupero post operatorio prolungato
alterazione della funzione respiratoria
alterazione dei riflessi protettivi delle vie aeree
64
TOF <0.9:
TOF <0.8:
TOF <0.7:
30/09/2015
66
TOF 0,7
TOF 0,9
30/09/2015
67
Vital
Capacity
Inspiratory
Force
Peak Exp.
Flow Rate
100
100
100
60%
91
70
95
70%*
97
82
92
80%
100
88
94
90%
100
91
95
100%
100
97
99
Control
=100
0,52
Hand grip, 5 s
0,51
Head lift, 5 s
0,51
General weakness
0,51
Leg lift, 5 s
0,5
Smile, swallow
or speak
0,47
0,2
0,4
0,6
0,8
30/09/2015
69
SUGAMMADEX?!
NEOSTIGMINA
EDROFONIO
PIRIDOSTIGMINA
74
NMBA-induced blockade of
acetylcholine receptor
Nerve
Nerve
Nerve
Muscle
Muscle
Muscle
Acetylcholine receptor
30/09/2015
Acetylcholine
Transmission
Non-depolarizing NMBA
75
Recommended
Dose (mg/kg)
Onset
of
Action
(min)
Duration
of Action
(min)
Site of
Action
neostigmine
0.01 to 0.05
7-11
60-90
postjunction
edrophonium
0.15 to 1.0
1-2
10-30
prejunction
pyridostigmine
0.02 to 0.5
Up to 16
60-120
postjunction
76
30/09/2015
Bradicardia 1
Ipersalivazione2
Broncospasmo3
Aumento delle secrezioni bronchiali4
Aumenta la frequenza urinaria
Nausea e vomito
Tachicardia
Secchezza fauci
Midriasi
Ritenzione urinaria
1 2 3 4 Van den brock et al. Eur Jour Anaesthesiol Suppl 1994;9:128-32
ChE, cholinesterase.
30/09/2015
*Atropine use causes dose-dependent adverse effects.
30/09/2015
80
CONTINUA
Per neutralizzare il curaro in modo
diverso ci si concentrati su alcune
sostanze che hanno alcune propriet
interessanti, gli AA. anglosassoni
hanno coniato il termine
HOST_GUEST (Ospite Ospitante)
come descritto nel 1961 da Linssen .
Curariform Drugs. The action of the different types and their
combinations on the neuromuscolar trasmission. PhD Thesis,
Nijmegen, The Netherlands: Radboud University 1961: 104-13
30/09/2015
81
Cyclodextrins
30/09/2015
82
30/09/2015
30/09/2015
84
30/09/2015
Abstracts from 7th International Neuromuscular Meeting, Belfast, June 2001.
30/09/2015
86
SIGNAL
n = 74 pts
aim:
70 mcg/kg (n=37)
time
from
1 or 2 PTCs
sugammadex
or
neostigmineglycopyrrolate
89
50
40
30
20
10
2.7
0
Bridion 4 mg/kg
Sugammadex
n = 37
95% CI (2.33.3 min)
CI, confidence interval; NEO, neostigmine; TOF, train-of-four.
30/09/2015
NEO 70 g/kg
n = 37
95% CI (35.759.5 min)
Data from Signal trial.
Jones RK et al. Anesthesiology. 2008;109:816-824.
90
17,6
18
16
14
12
10
8
6
4
1,4
0
Sugammadex 2 mg/kg
n = 48
95% CI (1.2-1.5 min)
30/09/2015
20
18,9
18
16
14
12
10
8
6
4
2,13
2
0
NEO 50 g/kg
n = 48
95% CI (12.7-26.4 min)
Sugammadex 2 mg/kg
n = 48
95% CI (1.9-3.0 min)
NEO 50 g/kg
n = 45
95% CI (12.2-25.5 min)
91
Prolonged duration
92
93
CONCLUSIONS
RESIDUAL NEUROMUSCULAR BLOCKADE (RNB) IS FREQUENTLY
OBSERVED DURING THE EARLY RECOVERY PERIOD FROM
GENERAL ANESTHESIA
SMALL DEGREES OF RESIDUAL PARESIS CAN PRODUCE A VARIETY
OF ADVERSE PHYSIOLOGIC EFFECTS
CHRURGIA LAPAROSCOPICA
Pathophysiological effects
CO2 pneumoperitoneum (Safran and Orlando AJS 1994)
head-up positioning and fluid deficit accounts for many of the adverse
effects in haemodynamics during laparoscopic cholecystectomy (Hirvonen et
al 2000).
Chirurgia Robotica
NMB-induced relaxation
maintained the
integrity of
pneumoperitoneum
without increased CO2
insufflation pressure
112
113
NMB facilitated
introduction of
instruments into the
cavity and extraction
of tissue.1
NMB created a more
open surgical field for
greater mobility.1,2
NMB=neuromuscular blockade.
1. Ogunnaike BO et al. Anesth Analg. 2002;95(6):17931805. 2. Welliver M et al. Drug Des Devel Ther. 2008;2:4959.
114
TOF=0 PTC=1-2
Dubois PE, Donnez O et al : Abstract Societ Francaise Anesthesie Reanimation, 09 2012. Societ Belge dAnesthesie
Reanimation 09 2012
CONCLUSIONS
LAPAROSCOPY IS A GROWING SURGICAL TECHNIQUE