1. Updates on Neuromuscular Blockage monitoring
Bernadette Henrichs, PhD, CRNA, CCRN
Barnes-Jewish College, St. Louis, MO

2. Disclosure Educational Speaker for Merck
Attended an Advisory Committee 6/2018 for Frezenius Kabi, a manufacturing company that makes neostigmine

3. muscle contraction Anatomy
Motor endplate
Neuron
Muscle

4. Physiology of Neuromuscular Junction
To make a muscle contract, Acetylcholine (ACh) is released from nerve and travels across synaptic cleft.
ACh then binds to ACh receptors on muscle.
ACh receptors open and the influx of ions causes the muscles to contract.
Ach is then broken down by the enzyme Acetylcholinesterase and is recycled.
Channels close, the endplate repolarizes, and the muscle cell relaxes.
Nerve
Acetylcholine
Muscle
Ach Receptors
K+ flows out of ACh receptor & sodium & calcium flow in.

5. How a Nondepolarizing Muscle Relaxant Works
The ACh receptor can be activated to open the channel and cause the muscle to contract ONLY when both alpha subunits are occupied by ACh.
When a non-depolarizing muscle relaxant is given, the muscle relaxant blocks ACh from occupying the receptors, leading to paralysis.
Nerve
Acetylcholine
Muscle relaxant
Muscle

6. Depolarizing vs non-depolarizing MRs
Can be classified by mechanism used to block acetylcholine from binding to its receptor, which leads to muscle relaxation.
Depolarizing MR (Non-competitive agonists); succinylcholine
Bind to Ach receptors, leading to an initial contraction (fasciculation), followed by relaxation
Not hydrolyzed by acetylcholinesterase, therefore, they can bind to Ach receptors for a longer time.
Leads to persistent depolarization of the motor endplate
Non-Depolarizing MRs (Competitive antagonists); rocuronium
Compete with Ach for receptor binding, blocking the action of Ach (blocking contraction and leading to muscle relaxation).

7. Is it necessary to monitor neuromuscular blockade?
Not monitoring neuromuscular blockade or not monitoring with a quantitative monitor increases incidence of postoperative residual
AANA: (Standard of Care #5)
Since 1989, states that if administering a NMB, monitoring must be done (however, use of quantitative monitoring not specified)
ASA:
Recognizes the importance but has not made a statement in regards to monitoring
AANA Does not address quantitative monitoring
Pelt M, Chitilian HV & Eikerman M: Multi-faceted initiative designed to improve safety of NM blockage. APSF Newsletter, February 2016, p

8. Qualitative Monitoring
Use of a peripheral nerve stimulator to determine TOF; cannot determine fade accurately
Subjective monitoring; tactile, visual testing
Even with 4/4 twitches, can still have up to 75% of receptors blocked
If 4/4 twitches and no post-tetanic fade, can still have a TOF ratio > 0.4 but < 0.9.
With 4/4 twitches, one cannot detect the ratio if not using acceleromyography
Not as accurate as a monitor that gives TOF ratio
Acceleromyography has been shown to slightly underestimate the degree of TOF when compared to the standard measure of mechanomyography.

9. Are clinical signs an effective way to assess reversal
Are clinical signs an effective way to assess reversal? Are they reliable?
No! Head lift, tidal volume, squeezing hand, clenching teeth on a tongue depressor are not good indicators of reversal-unpredictable and unreliable
TOF Ratio of 0.2: Pt can smile
TOF Ratio of 0.5: Pt can lift head off pillow
TOF Ratio of 0.6: TOF monitor: 4/4 twitches and no post-tetanic fade
TOF Ratio of 0.7: Pt can open eyes and squeeze hands but may have profound symptoms of muscle weakness, atelectasis-leading to pneumonia, visual disturbances, facial weakness, difficulty speaking/drinking
Positive predictor value for many of these clinical tests. Is about 0.5 or 50% - in other words, flip a coin and you have same results as the clinical test determining extubation accurately; (As good as flipping a coin)

10. Are clinical signs an effective way to assess reversal
Are clinical signs an effective way to assess reversal? Are they reliable?
TOF Ratio of 0.8: Pt can have impaired pharyngeal function and swallowing, increased risk of aspiration
TOF Ratio < 0.9: Pt may be able to bite down on tongue depressor but may have increased risk of postop hypoxemia, aspiration, obstruction on way to PACU, increased critical respiratory events, muscle weakness, delay in discharge
TOF Ratio > 0.9: Pt is now ready for extubation; no residual is likely to be experienced
Positive predictor value for many of these clinical tests. Is about 0.5 or 50% - in other words, flip a coin and you have same results as the clinical test determining extubation accurately.

11. Quantitative Monitoring
Once 4 twitches returned, a ratio gives the percent of 4th twitch compared to first twitch; given as a ratio
Gives ratio of amount of muscle fade; more accurate than a TOF
Acceleromyography, electromyography, mechanomyography
The fine differences that can be detected by using quantitative monitoring/objective monitoring offer major advantages over determining contraction strength visually or tactilely.
Research study by Murphy et al demonstrated that “unpleasant symptoms of muscle weakness are reduced and patient satisfaction is improved when quantitative monitoring is used in the OR.”
The new STIMPOD NMS450 Nerve Stimulator and TOF Monitor (~ $ )
TOF Ratio: Stimpod or the built-in GE Monitor are the only two (TOF Watch was discontinued in June 2016).
Acceleromyography has been shown to slightly underestimate the degree of TOF when compared to the standard measure of mechanomyography.
Murphy GS et al: Anesthesiology 2011; 115(5): ).

12. Quantitative Monitoring
Quantitative monitoring reduces likelihood of unrecognized significant residual muscle weakness in the postoperative period
Should improve patient safety
APSF has concluded that residual NMB is a common, under- appreciated condition that contributes to adverse events in the postoperative period
Current literature still reports similar occurrence rates as those reported in 1979

13. Where to Monitor Adductor Pollicus Muscle (Ulnar nerve)
Best and safer to monitor for recovery
Flexor Hallucis Brevis or Flexor Hallucis Longus Muscle (Posterior tibial nerve)
Use if you cannot monitor the ulnar nerve (Ex: arms tucked)
Corrugator Supercilli Muscle (Facial nerve)
Resembles diaphragm and laryngeal muscles; however, be cautious. You may have 4 twitches here but none at the wrist (most muscles still paralyzed)
Best to monitor for intubation

14. Monitoring the ulnar nerve

15. Monitoring the posterior tibial nerve

16. Monitoring the facial nerve
Recovery of supercilli muscle of the eye (eyebrow wrinkles) is comparable to recovery of the diaphragm
Temporal branch of facial nerve
Recovery of orbicularis occuli muscle of the eye (eyelid closure) is comparable to recovery of the adductor pollicis muscle
Zygomatic branch of facial nerve

17. Differential Resistance of Muscles to Neuromuscular Blockers
Most Sensitive; Least resistant
Pharyngeal Muscles
Adductor Pollicis Muscle (wrist)
(Monitor this for recovery)
Corrugator Supercilii Muscle
(Monitor this to know when to intubate)
Monitoring for recovery leads to increased incidence of postop residual compared to adductor pollicis m.
(These muscles return quickly like the diaphragm while the other muscles are still paralyzed)
Laryngeal Adductor Muscles
Diaphragm
Least Sensitive;
Most Resistant
See (eye monitoring) to intubate and feel (hand monitoring) to extubate

18. Train-of-Four Response

19. Train-of-Four Stimulation
Single Twitch
Single stimuli that is repeated; 0.2 msec in duration; used when Sux is given
Train-of-four stimulation (TOF)
4 stimuli at 2 Hz at intervals of 0.5 seconds
Can be repeated every 10 seconds
Post-tetanic stimulation
After getting no response with a TOF
Follow with a 5-second tetanic stimulation, wait 5 seconds, then give 1-Hz twitches & count number of twitches present
If at least one PTC, then < 10 minutes from return of first twitch
Wait 6 minutes before checking TOF again as increased Ach is at the motor endplate and your twitches may be falsely seen/stronger

20. Tetany Tetanic stimulation (50 Hz q 20 ms or 100 Hz q 10ms)
Usually used to assess residual NMB (TOF then tetany)
TOF tested; if 4 twitches, then tetany given to check for fade
Fade will occur with > 70-75% blockade for NDMR; With Sux, it will be greatly reduced but does not fade
Sustained response to tetanic stimulus is present when TOF ratio is > 0.7
Should not be repeated sooner than q 6 min due to increased ACh at the motor end plate and TOF may falsely present antagonism of NMB
At the end of the tetanic stimulus, there is an increase in the immediately available store of Ach
Subsequent twitch responses are transiently enhanced (post-tetanic facilitation)
Double burst or DBS, consists of 2 short bursts of 50-Hz tetanic stimulation separated by 750 msec. The duration of each square wave impulse in the burst is 0.2 msec. Although the number of impulses in each burst can vary, most commonly used is DBS with three impulses in each of the 2 tetanic bursts. In nonparalyzed muscle, the response to DBS is 2 short muscle contractions of equal strength. In the partly paralyzed muscle, the second response is weaker than the first. The absence of fade in DBS does not exclude residual neuromuscular blockade. (Miller, 2005: pg 1555).
While discussing tetanus here, post-tetanic facilitation should also be mentioned. Many anesthesiologists are fooled by post-tetanic twitches. For example, they will think of 2 post-tetanic twitches as being equivalent to 2 “real” twitches. Patients with only post-tetanic twitches will typically respond poorly to antagonism with neostigmine and end up with residual weakness in the PACU. This is one of the usual ways that we end up with partial curarization in the PACU.

21. At end of case, Monitoring DBS if unable to monitor TOF Ratio
Double burst stimulus normally done after patient has 4/4 twitches; done instead of checking tetany.
DBS: 2 brief, 50-Hz tetanic bursts 0.75 seconds apart.
D2 is checked for fade. The DBS ratio (D2/D1) approximates the TOF ratio if you don’t have a TOFR monitor; more sensitive than TOF and tetany.
However, difficult to determine if ratio is 0.60 or greater as the fade cannot be seen/felt.
TOF ratio is a better way to determine residual.
(Each burst consists of 3 stimuli that result in two sustained muscle contractions.)
Brull SJ & Kopman AF: Current status of NM reversal and monitoring. Anesthesiology Jan 2017; 126(1):

22. Summary

23. Summary

24. Monitoring Paralysis

25. How deep is the block? Depth of Block Twitch Response Shallow
TOF count with 4 twitches with fade
Moderate
TOF count with 1-3 twitches
3-4 twitches recommended if reversing with neostigmine
Deep
No TOF count but with a post-tetanic contraction (PTC)
Cannot reverse with neostigmine; can reverse with sugammadex
Extremely deep
No TOF count; No post-tetanic contraction
Normally, you should never have this deep a block

26. Why Reverse Neuromuscular blockade?
Postoperative residual occurs in 40%-80% of patients
Large clinical trial in > 500 patients reported:
45% of patients who received a single dose of intermediate acting NMB (without reversal) had a TOFR < 0.9 in PACU
Two hours after intermediate acting NMB given, TOFR was < 0.7 in 10% of pts and < 0.9 in 37% of patients.
Cautious titration of reversal using quantitative NM monitoring may decrease postop residual in PACU
APSF Newsletter Feb 2016

27. How do reversals work? Reversing a depolarizing MR
No reversal agent for a depolarizing agent (Succinylcholine); wears off with time; normally short-acting
Succinylcholine is metabolized by plasma cholinesterase (pseudocholinesterase); slower than acetylcholinesterase which metabolizes Ach at the NM junction.
Since plasma cholinesterase is not found in the NMJ, Sux’s action is terminated after it diffuses into the extracellular fluid (not when it is metabolized); takes about 4-11 minutes

28. How do reversals work? Reversing a non-depolarizing MR
Reverse with cholinesterase inhibitor or sugammadex
Originally, guidelines stated to have at least one twitch returned before giving anticholinesterase reversal.
If not, reversal may wear off and MR will still be on board, leading to the patient experiencing postoperative residual, a real concern.
New guidelines suggest having 3-4 twitches back before giving an anticholinesterase inhibitor for reversal; sugammadex reverses any type of block, including deep blocks (must have 1 or > PTCs)
Failure to give a reversal agent is the greatest risk for re-intubation in the next 48 hours postoperatively

29. How Acetylcholinesterase Inhibitors Work
When a muscle relaxant is reversed, an Acetylcholinesterase inhibitor may be given if 3-4 twitches back (Ex: Neostigmine).
This medication blocks the Acetylcholinesterase enzyme, preventing the breakdown of Ach.
This leads to more ACh at the neuromuscular junction, displacing the muscle relaxant and allowing ACh to bind to the receptors, leading to muscle contraction.
Nerve
Acetylcholine
Muscle
Ach Receptors
K+ flows out of ACh receptor & sodium & calcium flow in.
Buildup of ACh facilitates the transmission of impulses across the NM junction; this then kicks off the NDMR (rocuronium, etc)

30. Pathophysiology of Postoperative Residual
However, if not enough reversal is given, partial paralysis will occur due to some of the receptors still being occupied by the muscle relaxant.
Partial paralysis can also occur due to the slow onset of action of neostigmine.
If too much acetylcholinesterase inhibitor is given, there will be increased ACh at the site, leading to weakness due to cholinergic symptoms.
Nerve
Acetylcholine
Muscle
Ach Receptors
Have a ceiling effect-more of the drug will have no effect and can induce muscle weakness and pharyngeal muscle relaxation

31. Postoperative Residual
Defined originally as a recovery of the TOF ratio less than 0.7
Healthy volunteers described “uncomfortable symptoms” (visual disturbances, facial weakness, difficulty speaking/swallowing & generalized fatigue) with a TOF ratio
Postop residual now defined as TOF Ratio < 0.9
Remains a common but usually undetected occurrence in early postop period
Recent studies report similar results (40-80% of patients)
Not monitoring neuromuscular blockade or not monitoring with a quantitative monitor increases incidence
AANA Does not address quantitative monitoring
Pelt M, Chitilian HV & Eikerman M: Multi-faceted initiative designed to improve safety of NM blockage. APSF Newsletter, February 2016, p

32. How Sugammadex Works
Sugammadex is a cyclodextrin that can be used to reverse neuromuscular blockade.
Sugammadex has a different mechanism of action compared to acetylcholinesterase inhibitors.
Sugammadex reverses a muscle relaxant by encapsulating the muscle relaxant molecules, inactivating them.

33. Summary
If a muscle relaxant is given, monitoring with a PNS should be done. Ideally, a quantitative monitor should be utilized to determine TOF ratio.
If a muscle relaxant is given, it should normally be reversed.
A TOF ratio of 0.9 or > should be achieved before extubating the patient.
Dependence on clinical signs is associated with a high incidence of postoperative residual neuromuscular blockade.

34. Thank you!

35. references
Brull SJ & Kopman AF: Current status of NM reversal and monitoring. Anesthesiology 2017; 126(1):
Bulka, CM, Terekhov MA, Martin BJ et al: Nondepolarizing NMB agents, reversal and risk of postoperative pneumonia. Anesthesiology 2016; 125(4):
DeBaene B, Plaud B, Dilly MP, et al: Residual paralysis in the PACU after a single intubating dose of NDMR with an intermediate duration of action. Anesthesiology 2003; 98(5):
Gross-Sundrup M, Henneman JP, Sandberg Ws et al: Intermediate acting nondepolarizing NMB agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ October 2012; 1-14.
McGoldrick, KE: Residual NMB: Not just a theoretical concern. CRNA 2014; 36(25):

36. references
Murphy GS, et al: residual NMB and critical respiratory events in PACU. A & A July 2008; 107(1):
Murphy, GS & Brull SJ: Residual NMB: Lessons unlearned. Part I: Definitions, incidence, and adverse physiologic effects of NMB. A & A 2010; 111(1):
Murphy, GS & Brull SJ: Residual NMB: Lessons unlearned. Part II: Methods to reduce the risk of residual weakness. A & A 2010; 111(1):
Van Pelt, M, Chitilian, HV & Eikerman, M: Multi-faceted initiative designed to improve safety of neuromuscular blockade. APSF Newsletter February 2016;