Introductory Lecture for Anesthesiology Resident Education

1. Introduction to
Neuromuscular
Blockade
Edward B. Fohrman MD
Department of Anesthesiology
Northwestern University, Feinberg School of Medicine

2. Loosely based on a real case…
 You are asked to relieve your colleague
in OR-13 for a “routine” appy on a
healthy 25 y.o. ♂ after 1 mg/kg
Rocuronium for RSI under GETA with
sevoflurane, fentanyl, and 1:1 Air/O2.
 Just after you take over, you note the
HR at 128 beats/min and the BP is
200/100.
 What drug are you going to use to treat
this problem? (presuming u think it’s a
problem ☺)

3. “AWARENESS” during
anesthesia – preferably the
anesthesiologist…not the
patient!
• Incidence: 0.1-0.2%
• OB: 0.4 %
• Cardiac cases: 1-1.5%
•Trauma 11 – 43%
• 70-80% Awareness
reduction using BIS
BIS goal = 40-60
BIS > 80 = awake
Avidan et al. NEJM 358:1097-1108, 2008
Sandin et al. Lancet 335;707-711, 2000
Sebel et al. Anesthesiology 99;A-360, 1991
The use of muscle relaxant is an
independent risk factor for
AWARENESS!!!

4. History of NMB’s
 Descriptions of South American arrow poisons date
as early at the 16th century (curare)
 Claude Bernard determined site of action – mid 19th
century namely with experiments using d-
Tubocurarine (curare) derived from several plant
extracts; chondrodendron tomentosum and
strychnos toxifera
 Langley 1906 discovered the effects of nicotine on
the muscle end plate
 Dale et al. 1936 identified Ach as the
“neurotransmitter” at the NMJct
 1943 Neuromuscular blockade became part of
routine anesthesia administration to aid in surgery

5. Question
 You are on a hunting trip with a pal who
kills a wild boar with a curare tipped
arrow. Presuming you are not a
vegetarian and you are immune to
cysticercosis and mad cow disease,
would you eat the raw flesh of the
animal?
 (without fear of becoming paralyzed
after eating the curare laden meat???)

6. Considerations &
Characteristics of NMBs
 Speed of onset
 Duration of Action
 Route of elimination
 Associated side effects
 Patient’s underlying medical condition
 Burn, Sepsis, Renal/Liver failure, CVA,
Spinal cord injury (SCI), Myasthenia Gravis
and other neuromuscular disorders.

7. The Neuromuscular Junction

8. The Neuromuscular Junction

9. Nicotinic Ach Receptor

11. Neuromuscular Blockers
 Quaternary ammonium compounds that
have at least one positively charged
NITROGEN atom that binds to the
α-subunit of the nAChR.

12. Classification of NMB’s
Depolarizing
 Succinylcholine
Nondepolarizing
 Short Acting
 Mivacurium
 Rapacuronium
 Intermediate Acting
 Rocuronium
 Vecuronium
 Cisatracurium
 Atracurium
 Long Acting
 Pancuronium

13. What’s the best muscle
relaxant for my case?
 Onset
 (RSI vs. SIVI?)
 Duration of action/Rate of recovery
 (Marathon case or a quickie?)
 Neuromonitoring/Nerve monitoring?
 Planning to extubate at the end of the case?
 Metabolism and clearance
 Is the patient on any drugs that may interact
with my muscle relaxant?
 Is the patient have renal or liver disease?
 Does the patient have other medical conditions
of concern?

14. Classification of
Nondepolarizers
 AminoSteroids
 Pancuronium – bisquaternary aminosteroid
which most resembles structure of Ach
 Vecuronium & Rocuronium
 monoquaternary analogs of pancuronium
 Benzylisoquinoliniums
 Mivacurium, Cisatracurium, Atracurium
 Associated with histamine release (except cis)

15. Steroidal Nondepolarizers

16. Case
 You just “deep” extubated your patient
to avoid bucking on the tube after an
otoplasty. As you are moving the
patient to the gurney, the patient bucks
and coughs and begins to turn blue.
 More good news…your IV was
inadvertantly pulled out during the move
and is now dripping on the O.R. floor…
 What’s the problem and how are you
going to save the day?

17. Succinylcholine
• 2 Ach molecules linked by methyl groups
• Agonist action binds the alpha subunit and leads to
muscle contraction and refractory period
• Depolarizing block also called Phase I block
• Intubating dose: 1-1.5mg/kg (ED95 = 0.3mg/kg)
• Onset 30-60 secs and duration 5-10 minutes
• Defasciculating dose of nondepolarizer
• (5-10% of ED95 2-4 min prior) must increase sux dose by 70%
•Repeated doses > 3-5mg/kg >>> Phase II block
•Serum potassium (K+) by 0.5 to 1 mEq/L
• EJnAchR’s increase K+ ???

18. Why Sux is unique?
 The only Depolarizing blocker used
clinically today
 Most rapid onset of any other NMB
 Most rapid recovery/offset of any
NMB
 Most significant degree of vocal cord
paralysis/best intubating conditions
 Only NMB with rapid effects when
given I.M. in cases of no IV
access…IM dose?

19. Metabolism of Sux
 Rapidly hydrolized by Butylcholinesterase
(plasma cholinesterase)
 Pseudocholinesterases are produced in the
liver (sux dose in liver failure?)
 Only a small fraction of the original dose
reaches the neuromuscular junction

20. Succinylcholine
Succinylmonocholine + Choline
Succinic Acid + Choline

21.  22 y.o. 70 kg. male without significant
PMH/PSH undergoes a RSI for acute
appendicitis. 10 min after 1mg/kg of
sux, the patient receives a 30mg dose
of ROC.
 The case goes well and the surgeon
begins skin closure.
 TOF reveals that the patient still has no
twitches 1 hour after the last dose of
ROC….WHY?
CASE

22. Atypical Cholinesterase
 Check TOF after sux, (before NDNMB)
 Dx after a patient has a prolonged
response to sux or mivacurium (>1hour)
 Dibucaine Number
 Dibucaine – amide local anesthetic
 Inhibits normal enzyme by 80%
 Inhibits abnormal enzyme by only 20%

23. Variants of Plasma Cholinesterase and Duration of
action of Succinylcholine
Variants of Plasma
Cholinesterase Incidence
Dibucaine
Number
(% Inhibition of
enzyme activity)
Duration of
succinylcholine
induced
neuromuscular
blockade (min)
Homozygous
Typical
Normal 70-80 5-10
Heterozygous 1 in 480 50-60 20
Homozygous
Atypical
1 in 3200 20-30 60-180
Stoelting & Miller, Basics of Anesthesia. 2007

24.  You are on overnight Neuro ICU
call when you are called to
intubate the following patients…
75 y.o. male s/p ischemic CVA 3 weeks
ago with residual left hemiparesis
21 y.o. female PMH - MVA 4 years ago with
incomplete T4 level –
urosepsis/pneumonia and SpO2 89%
18 y.o. male s/p GSW to head, in barb
coma w/ vecuronium gtt x 7 days who was
inadvertantly extubated by the RN…

25. Sux: Adverse side effects
 Cardiac dysrhythmias
 Sinus brady, Jct brady, Sinus arrest
 Fasciculations
 Hyperkalemia
 Myalgia (especially in outpatients)
 Myoglobuinuria - MH
 Increased intraocular pressure (not more than bucking)
 Increased intragastric pressure
 Trismus - Masseter muscle rigidity common in peds (4%)
 Associated with subsequent development of MH
 Note: 1mg/kg Sux does NOT increase ICP (Kovarik et al.
Anesthesia&Analgesia, 1994;78:469-73

26. Up/Down Regulation of nAChR
Martin and Richtsfeld, Anesthesiiology, 2006;104:158-69

27. “Extrajunctional Receptors”
Normal
Denervation

28. Effect of Sux on denervated muscle
Martin and Richtsfeld, Anesthesiology, 2006;104:158-69

29. Martin and Richtsfeld, Anesthesiology, 2006;104:158-69

30. Nondepolarizing NMBs
 Competitive Inhibition of Ach
 No fasciculations
 Bind α-subunit of the nAchR
 Quaternary ammonium group
 Water soluble, highly ionized, at physiologic pH
 Poor lipid solubility:
 Do NOT cross - BBB, Placenta, renal tubular
epithelium, GI tract (ineffective orally)

31. Pharmacokinetic & pharmacodynamic
effects of nondepolarizers
 Variable responses due to:
 Volatile agents
 Other drug interactions/effects:
 Effect of different disease states:
 Hepatic, Renal, CNS, Neuromuscular etc.
 Hypothermia
 Hypovolemia
 Age?
 Similar dose response curves in elderly vs.
young adults…

32. Drugs that affect NDNMBs
Enhanced Effects Diminished Effects
Volatile Anesthetics
Aminoglycoside ABX
Local Anesthetics
Cardiac
Antiarrhythmics
Dantrolene
Magnesium
Lithium
Tamoxifen
Calcium
Corticosteroids
Anticonvulsants
Burn injury
CVA

33. What if I use more than one
nondepolarizer?
 Combinations of two nondepolarizing neuromuscular blocking drugs are either additive or synergistic, depending on
which two drugs are involved. Addition occurs when the total effect equals that of equipotent doses of each drug. For
instance, pancuronium and vecuronium have an additive interaction.103 An ED95 of either pancuronium (0.07 mg/kg) or
vecuronium (0.05 mg/kg) yields 95% blockade. Half the ED95 of pancuronium (0.035 mg/kg) administered with half the
ED95 of vecuronium (0.025 mg/kg) will also produce 95% block. However, some combinations are synergistic, that is
their combined effect is greater than if an equipotent dose of either one of the constituents is given alone. For example,
cisatracurium (ED95 = 0.05 mg/kg) and rocuronium (ED95 = 0.3 mg/kg) will produce a greater blockade than equipotent
amounts of each drug given alone. To get 95% block, not one-half but approximately one-fourth the ED95 of each drug
needs to be given together, that is cisatracurium, 0.0125 mg/kg with rocuronium, 0.075 mg/kg.104 Generally,
combinations of chemically similar drugs—for example, pancuronium–vecuronium, d-tubocurarine–metocurine, and
atracurium–mivacurium—have additive effects. Combinations of dissimilar agents tend to show potentiation, but the rule
is not always followed. For example, mivacurium and cisatracurium show synergism,104 while vecuronium and
atracurium show very little, if any. The first such synergism was demonstrated for pancuronium–metocurine
combinations, and the mixture has less cardiovascular effects than either drug alone for the same neuromuscular
block.64 The use of combinations may be recommended to reduce cost, and this might be advocated for cisatracurium–
rocuronium mixtures, which show synergism. Another reason to use mixtures of drugs is to take advantage of the
properties of two drugs. For example, synergism occurs between mivacurium and rocuronium, and the mixture retains
the fast onset of rocuronium, while having the short duration of action of mivacurium.105
 The mechanism by which two drugs produce a greater effect than either one alone is unknown, except in rare cases. For
example, synergism is expected between mivacurium and pancuronium, because of the inhibition of plasma
cholinesterase that pancuronium produces, thus accentuating the effect of mivacurium. However, such a simple
mechanism is absent in most cases. Administration of a combination of relaxants does not affect the degree of protein
binding of either drug. Surprisingly, when drug mixtures are applied to receptors in vitro, no potentiation is observed.106
Perhaps the interaction occurs via presynaptic receptors or some other, unknown, mechanism.
 Interactions of a different nature occur when administration of a nondepolarizing agent is followed by injection of another
nondepolarizing agent. Usually, the duration of action of the second agent is that of the first drug given. For example, if
mivacurium, a short-acting agent, is given after mivacurium, it has a duration of action of 12 minutes. However, if the
same dose of mivacurium, 0.05 mg/kg, is given after rocuronium, its duration of action is prolonged to 42 minutes.107
On the contrary, if mivacurium is the first drug, rocuronium has a short duration of action. Thus, switching from a long- or
intermediate-duration agent to a shorter duration drug to obtain paralysis of short duration at the end of a case will not
provide paralysis of short duration. The reason why the characteristics of the first agent given are determinant is that the
size of the loading dose is greater than that of the maintenance dose, so that even when the second dose is given, the
majority of receptors is still occupied by the first drug.

34. Cardiovascular effects
NDNMBs
 Histamine mediated
 Cardiac muscarinic receptors (m2)
 Autonomic ganglia nicotinic
receptors

35. Hypoxic ventilatory response
in unanesthetized volunteers
TOF ratio = 0.7
• difficulty speaking, swallowing,
sitting up, facial weakness,
diplopia
TOF ratio = 0.9
•Esophageal and pharyngeal tone
return to baseline
Residual paralysis decreases
hypoxic ventilatory drive(HVR)
due to inhibition of the carotid
body neural response to hypoxia.
Vecuronium decreases carotid
sinus nerve activity in a dose
related fashion, due to its
interaction with neural nAchR
Eriksson et al. Acta Anaesthesiol Scand 36:710, 1992
Eriksson et al. Anesthesiology. 78:693–699, 1993

36. Question
 Over 50% of allergic reactions under
anesthesia are due to which of the
following?
A. Antibiotics
B. Latex
C. NSAIDs
D. Muscle Relaxants

37. Allergic Rxn’s
 NMBs are the triggering drugs for >50% of
anaphylactic rxns during anesthesia
 0.004 to 0.1% incidence for all anesthetics
 Sux is most common NMB in anaphylaxis
 Roc is most common Nondepolarizer
implicated in IgE mediated allergic rxn’s

38. Peak effect of NMB’s at 1x ED95
Kopman et al. Anesthesiology 90:425, 1999
1 x ED95

39. Pancuronium (Pavulon)
 ED95 = 0.05-0.07mg/kg
 Intubating dose = 0.05-0.2mg/kg (2min onset)
 Maintenance dose = 0.01-0.02mg/kg
 Onset = 3-5 min
 Duration = Long acting (60-90 min)
 80% unchanged in urine
 30%-50% plasma clearance in Renal failure
 10%-40% hepatic deacetylation
 Atropine like effect 10-15% HR, MAP, and
Cardiac output (via m2 action - Beta Blockade
doesn’t block this effect)

40. PANCURONIUM
Ach Moieties
Most chemically similar nondepolarizer to Ach

41. Vecuronium (Norcuron)
 ED95 = 0.05mg/kg
 Dose = 0.1mg/kg
 Onset = 3-5 min
 Duration = 20-35 min (Intermediate)
 Elimination
 1 active metabolite, 3-desacetylvecuronium
 50-70% as potent as parent drug
 Hepatic and renal excretion
 Biliary secretion
 Small increase in duration in renal failure
 No circulatory effects, No vagal effects,
 Lyophilized powder 10mg in 10ml (1mg/ml)
 Lasts 8 hours after reconstitution

42. Rocuronium (Zemuron)
 PPT in STP (“rock”)
 ROC is the ONLY NDNMB with an “ON LABEL”
indication for RSI !!!
 ED95 = 0.3mg/kg
 Onset = 1-2 min / Duration = 20-35 min
 Intubating dose is 1-1.2mg/kg (3-4x ED95)
 (mimics duration of pavulon >1hr)
 Maintenance dose is 0.6mg/kg
 Clearance unchanged in BILE
 Excretion = 30% renal

43. Atracurium
 Mixture of 10 stereoisomers
 ED95 = 0.2 mg/kg
 Onset = 3-5 min
 Duration = 20-35 min (intermediate)
 Clearance
 1/3 Chemical: Hofmann elimination
 Spontaneous nonenzymatic degradation
 2/3 Biologic: Ester hydrolysis by nonspecific plasma
esterases
 Both pathways produce a metabolite called
LAUDANOSINE - (EPILEPTOGENIC metabolite)
 Higher doses = hemodynamic changes
(Tachycardia and Hypotension) -histamine release

44. Cisatracurium (Nimbex)
 Cis-stereoisomer of Atracurium
 ED95 = 0.05mg/kg
 Onset = 3-5 min
 Duration = 20-35 min
 Maintenance dose = 0.1mg/kg
 Intubating with 4x ED95 (0.2mg/kg) achieved intubating
conditions in 1.5 min in only 87%
 Clearance is principally by Hofmann Elimination
 Lower laudanosine levels in plasma c/w atracurium
 Dose and duration unaffected in Hepatic/Renal
failure
 No hemodynamic effects/No Histamine release

45. Mivacurium
 ED95 = 0.08 mg/kg
 Onset = 2-3 min
 Duration = 12-20 min (Short)
 Histamine release at 2-3x ED95
 2 of 3 isomers degraded by:
 plasma cholinesterase
 Avoid Miv and Sux in atypical cholinesterase patients
 Neostigmine (AChE) can slow hydrolysis of Miv
 Moderate levels of muscular blockade with miv are
actually reversed by Neostig likely b/c Neostig is a
better inhibitor of True Acetylcholinesterase > Plasma
(Pseudocholinesterase)
 Abbott discontinued “Mivacrap” June 2006
 Business decision…

46. Rapacuronium (Raplon)
 Aminosteroid compound that was introduced for
clinical use in 1999
 Withdrawn in 2001 because of rare, but severe
cases of bronchospasm
 Following 1.5 mg/kg, good to excellent intubation
conditions were produced at 60 seconds, clinical
duration (25% T1 recovery) occurs in 17 minutes
and spontaneous recovery to train-of-four ratio of
0.7 occurs in 35 minutes.
 Able to reverse immediately with Neostigmine
 Bronchospasm mediated by M3>M2 effects (not
allergic)

47. Sugammadex: New milestone?

48. Sugammadex
Naguib, M. Anesth Analg 2007;104:575–81

49. TOF Recovery: Roc+Sugammadex vs. Sux
3 min
ROC 1.2mg/kg
Sugammadex 16mg/kg
Sux 1mg/kg
Naguib, M. Anesth Analg 2007;104:575–81

50. TOF monitoring
Barash, Cullen and Stoelting, Clinical Anesthesia 5th Ed. 2006

51. TOF: How much current (mA)?
Barash, Cullen and Stoelting, Clinical Anesthesia 5th Ed. 2006

52. TOF Ratio
2 sec
A
B
= A / B

53. Depolarizing vs.
Nondepolarizing TOF
Depolarizers NOT “FADE” AWAY
Miller’s Anesthesia 6th Ed. 2005

54. Depolarizing Block
0.3
Miller’s Anesthesia 6th Ed. 2005

55. PHASE II BLOCK
 End plate is repolarized, but still doesn’t
respond to Acetylcholine
 “Desensitization neuromuscular blockade”
 Mechanism unknown
 Resembles nondepolarizing block (fade
to tetanic stimulation and Post-tetanic
potentiation)
 Reversed by AchE-I’s

56. Why Double Burst?
 2 bursts of three stimulations 750msec apart is perceived as 2
distinct twitches
 Improved ability to detect a TOF ratio of <0.3, but still doesn’t
insure ability to conclude TOF ratio >0.7
Miller’s Anesthesia 6th Ed. 2005

57. DBS
Miller’s Anesthesia 6th Ed. 2005

58. Tetanus
 Tetanic (sustained)
stim at 50Hz for 5 secs
 Nondepolarizers –
Fade with tetany
 Depolarizers – Uniformly ↓
amplitude at any level of
blockade, but no fade,
(unless Phase 2 block
occurs).
Barash, Cullen and Stoelting, Clinical Anesthesia 5th Ed. 2006
DRUG

59. • 120 Patients undergoing gyne or general surgery with rocuronium
and reversed with neo/glyco
• TOF at time of extubation was measured after clinical assessment of
extubation criteria and then again after admission to the PACU
• Immediately before tracheal extubation, the mean TOF ratio was
0.67
• 70 (58%) had aTOFratio < 0.7
• 105 (88%) had a TOF ratio < 0.9
•Significantly fewer patients had TOF ratios 0.7
(9 subjects, 8%) and 0.9 (38 subjects, 32%) in the
postanesthesia care unit compared with the operating room
Murphy et al. Anesth Analg 2005;100:1840–5

60. Which muscles recover first?
Barash, Cullen and Stoelting, Clinical Anesthesia 5th Ed. 2006

61. Reversal with AChE-Inhibitors
IF THERE ARE NO
TWITCHES, DO NOT
ATTEMPT
REVERSAL!

62.  Optimally, reversal agents should be given, when
four twitches are visible, which corresponds to a first-
twitch recovery of >25%. For this assessment, using
the adductor pollicis is preferable.
 Spontaneous respiration is NOT a sign of adequate
neuromuscular recovery.
 The diaphragm recovers earlier than the much more sensitive
upper airway muscles, which recover, on average, at the same time
as the adductor pollicis.
 To prevent upper airway obstruction after extubation,
it is preferable to use the adductor pollicis, instead of
the more resistant muscles of the hypothenar
eminence or those around the eye.
WHY USE THE ADDUCTOR POLLICIS?

63. Clinical correlation & TOF
Adductor pollicis TOF testing in awake volunteers
after tx with Mivacurium
Barash, Cullen and Stoelting, Clinical Anesthesia 5th Ed. 2006

64. Case
 You just gave report on an otherwise healthy
34 y.o. male following a routine appy under GA
 10 minutes after you leave the PACU, the RN
calls and says that patient is bradycardic with
a HR of 38
 What will you do?

65. AChE-Inhibitor/
Anticholinergic
IV Dose
mg/kg
Onset/
Peak
Cross BBB
Edrophonium
(Tensilon)
0.5 - 1 30-60 sec
1-2 min
No
Neostigmine
(Prostigmin)
0.04-0.08 <3 min
7-11 min
No
Pyridostigmine
(Mestinon)
0.1 - 0.25 2-5 min
15-20 min
No
Physostigmine
(Antilirium)
0.01-0.03 3-8 min
5-10 min
Yes
Glycopyrrolate
(Robinul)
Neo 0.01-0.05
Pyrid 0.25
<1 min/5 min
2-3hr duration
No
Atropine Neo 0.05-0.15
Edro 0.5-1
<10 sec/2min
1-2hr duration
Yes
Stoelting & Miller, Basics of Anesthesia. 2007

66. Anticholinesterase Reversal
TOF Fade AchE-I / IV Dose
mcg/kg
AntiCholinergic/
IV Dose mcg/kg
None n/a NOT
Recommended
NOT
Recommended
≤ 2 ++++ Neostigmine 70 Glycopyrrolate 7
or Atropine 15
3-4 +++ Neostigmine 40 Glycopyrrolate 7
or Atropine 15
4 ++ Edrophonium 500 Atropine 7
4 None Edrophonium 250 Atropine 7
Stoelting & Miller, Basics of Anesthesia. 2007

67. What is the maximum dose
of neostigmine?
60 - 80 ucg/kg

68. Speed of TOF Recovery
Edro > Neostig > Pyrido
Barash, Cullen and Stoelting, Clinical Anesthesia 5th Ed. 2006

69. Case
 A small special forces unit on a secret
mission in an undisclosed country all
develop N/V, diarrhea, urinary
incontinence, pinpoint pupils, wheezing,
dizziness, drooling, and weakness.
 A patient with myasthenia gravis presents
to the E.R. with all the same symptoms…
 Explanation???

70. Side effects of AchE-Inhibitors
 Anticholinesterases lead to increased Ach
EVERYWHERE!
 Cholinergic Syndrome “DUMBBELLS”
 Defecation/Diarrhea
 Urination
 Meiosis
 Bradycardia
 Bronchoconstriction
 Emesis/Erection
 Lacrimation
 Laxation (weakness)
 Salivation

71. Case
 You take over a lap chole.
The pt. is a mildly obese
o/w healthy 42 y.o.
female. After giving “full
reversal” the patient is
extubated. She begins to
desaturate and appears to
be in laryngospasm. You
are unable to ventilate the
patient…what is your next
move?
Duration of SUX?
Dose of ROC?

74. Questions?