The normal neuromuscular junction (NMJ) consists of a presynaptic neuron, a Schwann cell (covering the neuron), and a postsynaptic muscle fiber. The presynaptic neuron stores and releases ACh. ACh receptors exist at both junctional AND extrajunctional areas of muscle fibers, however their density is ~ 100-1000x higher at the NMJ.
When a nerve impulse reaches the end of a presynaptic neuron, N-type Ca++ channels increase the intracellular calcium concentration, which causes the synaptic vesicles to release ACh into the endplate. These ACh molecules then bind to the junctional receptors (note that these are nicotinic receptors, muscarinic receptors are present in autonomic ganglia and in the CNS), allowing for Na+ and Ca++ influx into the muscle cell, which ultimately leads to contraction. Aceytlcholinesterases quickly degrade available synaptic ACh, preventing prolonged contraction.
Postjunctional receptors (α, α, β, δ, and ε) exist only at the endplate, while extrajunctional receptors (ε units are replaced with γ) are present throughout the skeletal muscle. Normal neuronal activity suppresses extrajunctional receptors, however inactivity, sepsis, denervation, trauma, and/or burn injury can lead to proliferation. These receptors stay open longer than junctional receptors, and account for the hyperkalemic response to NMDBs and resistance to NMBDs in certain patient populations.
Of the depolarising agents, succinylcholine is a clinically used agent whose structure consists of two acetylcholine molecules linked back-to-back at the methyl ends.
Non-depolarizing NMBDs are either aminosteroids (pancuronium, vecuronium, rocuronium) or benzyltetrahydroisoquinoliniums (atracurium, cisatracurium, mivacurium). Non-depolarizing NMBDs generally have quartenary ammonium groups which are ionized, and therefore water soluble compounds. Because of their cationic structures, they cannot easily cross lipid membranes.
Pharmacokinetics and Pharmacodynamics
Succinylcholine is not degraded by acetylcholinesterase, but rather by plasma cholinesterases.
The pharmacokinetic profile of non-depolarizing NBMDs is affected by body temperature, volume status, and hepatic (rocuronium) or renal (pancuronium) disease. Elderly patients and young adults seem to have near-identical dose response curves [Duvaldestin Anesthesiology 56: 36, 1982; Matteo Anesth Analg 77: 1193, 1993]
|Elimination is as follows:|
|Vecuronium||80% hepatobiliary, 10-20% renal|
|Pancuronium||70-80% renal, 15-20% hepatobiliary|
The activity of these drugs is enhanced by volatile anesthetics (thus less drug is required) as well as local anesthetics, antiarrhythmic drugs, and aminoglycosides. Steroids, calcium, and phenytoin may actually reduce their activity [Richard A et al. Anesth Analg 100: 538, 2005;
FREE Full-text at Anesthesia & Analgesia].
Interactions with Non-Depolarizing NMBDs
|Enhanced Response (4A’s)||Diminished Response|
Burn victims and patients suffering from stroke may be resistant to non-depolarizing NMBDs (likely due to extrajunctional receptors). Non-depolarizing NMBDs may produce mild cardiovascular effects due to histamine release. Rarely, asthmatics who take steroids, or critically-ill patients with MOF may manifest prolonged skeletal muscle weakness, which can occasionally last for weeks or months.
NMDB Use (Dosing, Onset, etc.)
|Neuromuscular Blocking Drugs|
|Dose (mg/kg)||Onset (m)||Duration (m)||Other (hist?)|
|SCh||0.5 – 1.5||0.5 – 1.0||5 – 10||Beware K+ release|
|Roc||0.6 – 1.2||1 – 2||20 – 35||Liver excr/met|
|Miv||0.25||2 – 3||12 – 20||Enzymatic degr|
|Vec||0.08 – 0.1||3 – 5||20 – 35||Liver excr/met|
|Pamc||0.1||3 – 5||60 – 90||80% renal excr|
Note: Dunn Table 12.1 states that rocuronium lasts 40-150 mins [Dunn PF. Clinical Anesthesia Procedures of the Massachusetts General Hospital, 7th ed. LWW (Philadelphia), p. 196, 2007]
NMBDs are the triggering drugs for more than 50% of anaphylactic and anaphylactoid reactions during anesthesia, most commonly SCh (a large Norwegian case study suggested that 93% of incidents involved NMBDs [Harboe Anesthesiology 102: 897, 2005]). The incidence is between 1:1000 and 1:25,000 anesthetics. Additionally, there may be cross reactivity among the non-depolarizing NMBDs, as the quartenary ammonia group may be the offending agent.
Peripheral nerve stimulators are theoretically the most reliable monitoring method, although visual estimates of TOF are unreliable. Most commonly, electrodes are placed over the ulnar nerve (elbow or wrist, recovers relatively late) or facial nerve (lateral face, recovers relatively early) – the orbicularis oculi (CN VII) more closely reflects blockade of the larynx than the adductor pollicis (ulnar) [Meistelman Can J Anaesth 39: 665, 1992], which is important because while non-depolarizing NMBD onset is more rapid at the vocal cords, it is less intense as compared to peripheral muscles (by contrast, onset of SCh is identical between laryngeal and peripheral nerves) [Sayson Anesthesiology 81: 35, 1994]. Note that the negative pole (black) should be placed distally for best response.
In general, a 90% reduction of the twitch response or elimination of 2 or 3 in the TOF should suffice for intra-abdominal surgery. One does not need to administer NMBDs until past the point of zero twitching – in fact, if no twitches are observed, NMBD should be withheld until at least some motor activity recovers.
Recent A&A Issue Highlighting NMB (Eight Editorials and Manuscripts)
In July of 2010, Anesthesia & Analgesia (Volume 111, Issue 1) published five editorials and three manuscripts regarding neuromuscular blockade, the sum of which suggest that quantitative train of four monitoring should be routine [Viby-Mogensen J, Claudius C. Anesth Analg 111: 1, 2010; PubMed Link; Miller RD, Ward TA. Anesth Analg 111: 3, 2010; PubMed Link; Donati F. Anesth Analg 111: 6, 2010; PubMed Link; Kofman AF. Anesth Analg 111: 9, 2010; PubMed Link; Futter M, Gin T. Anesth Analg 111: 11, 2010; PubMed link; Naguib M, et al. Anesth Analg 111: 110, 2010; FREE Full-text at Anesthesia & Analgesia; Murphy GS, Brull SJ. Anesth Analg 111: 120, 2010; FREE Full-text at Anesthesia & Analgesia; Murphy GS, Brull SJ. Anesth Analg 111: 129, 2010; FREE Full-text at Anesthesia & Analgesia]
Train of Four
Four stimulations at 2 Hz (0.5 seconds between bursts). With non-depolarizing NMBDs, the height of the 4th twitch should be lower than the 1st. A non-depolarizing TOF > 0.7 suggests return to control height. A TOF < 0.3 for SCh suggests phase II blockade (similar to NMBD). Usually, SCh will not display a “fade” between the 1st and 4th stimulations.
Questionable Utility of TOF
In addition to being inaccurate (when estimated visually or manually), some authors have criticized the increase in acceptable TOF – Debaene states argues the range of “acceptable” TOF for recovery has gradually increased from 0.7 to 0.9, even though there are no studies comparing the outcome using 0.7 versus 0.9 [Debaene et. al. Anesthesiology 98: 1042, 2003]. This of course is countered by Glenn Murphy and Sorin Brull’s statement that “Volunteer studies have demonstrated that small degrees of residual paralysis (train-of-four ratios 0.7-0.9) are associated with impaired pharyngeal function and increased risk of aspiration, weakness of upper airway muscles and airway obstruction, attenuation of the hypoxic ventilatory response (approximately 30%), and unpleasant symptoms of muscle weakness” [Murphy GS, Brull SJ. Anesth Analg 111: 120, 2010]
Because TOF is unreliable both visually or manually, one can give two bursts of 3, separated by 750 msec, which is perceived as two separate twitches. By not feeling the second twitch, the observer’s ability to test for a TOF < 0.3 is improved, however the ability to check for TOF > 0.7 is unchanged [Kopman Anesthesiology 86: 765, 1997]
5 seconds of 50Hz. With a non-depolarizing NMBD, the response fades. With SCh, the response is table but attenuated. If a sustained response is found, then the TOF is probably > 0.7.
Summary: Monitoring NMBDs
Summary: Monitoring NMBDs
- Threshold for TOF: need at least 0.9 to minimize risk of post operative complications
- Assessment of TOF: visually or manually unreliable – must use quantitative monitoring
- TOF < 0.3: to test for TOF < 0.3 (if quantitative TOF not available), use double burst testing
- TOF > 0.7: to test for TOF > 0.7 (if quantitative TOF not available), use tetanus
Two ACh molecules linked by methyl groups. Succinylcholine is not, however, degraded by acetylcholinesterase, but rather by plasma cholinesterases.
0.5 – 1.5 mg/kg to produce paralysis within 30-60 seconds, lasting 5-10 minutes. Can pretreat with 5% of the ED95 for a non-depolarizing NMBD 2-4 minutes prior, which will blunt the fasciculations (note that SCh will then need to be increased by 70%, or just give 1.5 mg/kg).
SCh produces a “phase I blockade” i.e., a depolarizing blockade. Full recovery usually occurs within 10-15 minutes.
A phase II blockade (repolarized membrane is still non-responsive, resembling the effects of non-depolarizing NMBDs) can occur at doses in excess of 2-5 mg/kg but the mechanism is unknown. Potassium will increase by about 0.5 mEq/L on average, however if extrajunctional receptors have proliferated, this increase can be much more substantial. Interestingly, a phase II block can be partially (or sometimes completely) reversed with neostigmine, and displays fade after tetany (also similar to non-depolarizing NMBDs). One potential mechanism of action is densitization of the AChR. Recovery of phase II also occurs within 10-15 minutes.
Plasma cholinesterase strongly influences the duration of action, and liver function must be markedly decreased before decreased protein synthesis affects this drug.
Patients with atypical cholinesterase will have prolonged duration – in order to test for this, administer dibucaine (amide anesthetic which inhibits normal enzyme activity by 70-80%) in vitro – normal plasma cholinesterase activity will be inhibited 80% by addition of dibucaine. 20-30% inhibition suggests homozygous atypical plasma cholinesterase, whereas 50-60% inhibition suggests a heterozygote. Risk of homozygous atypical cholinesterase is 1:2800. Even more rarely, some patients with atypical cholinesterase may have a normal dibucaine test but be inhibited by fluoride, so test for this if indicated.
FDA BLACK BOX WARNING IN YOUNG MALES. SCh should not be given 24 to 72 hours after burns, trauma, or denervation [Gronert Anesthesiology 43: 89, 1975], and should also be avoided in children as it has been shown to cause arrest in boys with undiagnosed muscular dystrophy [Rosenberg Anesthesiology 77: 1054, 1992].
SCh activates muscarinic receptors, leading to bradycardia, junctional rhythms, and even sinus arrest – in children this an occur after one dose, but in adults is most common when a second dose is administered 5 minutes after the first (i.e., beware repeating SCh in adults q5min, if required, pretreat with 0.4 mg atropine IV). Risk can be decreased by pretreating with non-depolarizing NMBDs or by administering atropine. Interestingly, SCh can mimic ACh at other sites and also cause increased SBP and HR.
Normal increase is 0.5 – 1.0 mEq/mL. Risk of serious hyperkalemia usually peaks 7-10 days after insult, but increased K+ release may occur as soon as 2-4 days after denervation injury, or after several days of immobility. Duration of risk has not been adequately characterized but is suspected to be for 3-6 months. Our current understanding of this phenomena is incomplete [Martyn Anesthesiology 104: 158, 2006]. Note that renal failure itself does not place patients at risk for exaggerated release [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier (China), 2007] and SCh can be administered, although the margin for error is lower. Dunn agrees that renal failure itself does not increase the risk of SCh administration as long as hyperkalemia is well-controlled [Dunn PF. Clinical Anesthesia Procedures of the Massachusetts General Hospital, 7th ed. LWW (Philadelphia), 2007]
Pretreatment with a non-depolarizing NMBD (ex. 3 mg rocuronium) or with lidocaine can reduce but will not totally eliminate myalgias [