History of Train-of-Four (TOF)

History of TOF Infographic 2b

TOF History
How and Why We Monitor Neuromuscular Blockade

 

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1945: The use of neuromuscular blocking agents (NMBAs) was gaining popularity, but little guidance is provided regarding how to evaluate the depth of blockade or recovery. The ability to perform a ‘head lift’ is considered evidence that a patient can breathe adequately [1].

1954: In their seminal paper, Beecher and Todd report that mortality was six times higher among individuals receiving muscle relaxants prompting clinicians to find a better way to monitor the effects of NMBAs [2].

1958: Christie and Churchill-Davidson describe a small battery-powered peripheral nerve stimulator (PNS) that they used to study the effects of various muscle relaxants and their acetylcholinesterase antagonists on neuromuscular transmission in patients [3, 4, 5].

 

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1965: Two commercially available PNS units are introduced, and after extensive experience using one of the devices, Katz reports two observations that proved prescient:

  • Due to the variability in patient response to neuromuscular blockers, using the individual patient’s observed responses is more effective than calculating redoses based on the patient’s weight.
  • A clinical device to routinely and continuously measure neuromuscular blockade is needed [6, 7].

While the introduction of the peripheral nerve stimulator marked a significant advancement in monitoring, there was still no objective way to measure the degree of block.

1971: In a series of groundbreaking articles, Ali et al., introduce the train-of-four (TOF) stimulation sequence, ushering in the era of quantitative neuromuscular monitoring.

More About TOF


In the first of a two part article, Ali et al. compares three ratios: (a) the height of the first response in the train of four (T1) to the height of a control response, (b) the height of the second response (T2) to the height of the first response (T1) -- “T2/T1”, and (c) the height of the fourth response (T4) to the height of the first response --“T4/T1.”  

   

As shown in Figures 2 and 3, ratio (c) T4/T1 was highly correlated with both ratio (a) and ratio (b), while the low regression line demonstrated that ratio (c) was the most sensitive index of the degree of block [8]. 

In Part II of the series, Ali investigates whether the ratios correlated with a common clinical assessment of recovery—a head lift. Ratio (c) (T4/T1) proved to be a sensitive indicator of clinical recovery. No patients with a TOF ratio <40% were able to lift their head off the pillow, while all patients with a TOF ratio >60% were able to lift their heads for a period of 3 sec or more.

As described by Ali and as it is used today… 

TOF sequence consists of four stimuli spaced 500 ms apart. The evoked response is quantified as a TOF count or a TOF ratio. 

TOF count (TOFC) is the number of evoked responses (a number between 0 and 4). 

TOF ratio (TOFR) is calculated when there are four responses and is a measure of T4/T1.  

In the absence of neuromuscular blocking drugs, the TOF ratio is 1.0. During a partial non-depolarizing block, a progressive decrease in the amplitude of each twitch (fade) is observed [9]. During a moderate block, a patient may have fewer than four twitch responses. These twitches are counted from 0 to 3 and are referred to as a TOF count. 

Major advantages of the Train-of-Four (TOF) sequence:
1. Acts as its own control, no need for control height. 
2. Less susceptible to time-dependent variables (positioning, skin impedance). 
3. Can be performed on a patient with existing neuromuscular blockade. 

 

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1975: Ali et al. determine that a TOF ratio of 60% or higher indicates sufficient recovery of respiratory muscles, and any decline in pulmonary function is likely due to delayed recovery from anesthesia [10].


1977: Brand et al. examine the correlation between train-of-four (TOF) and clinical signs of recovery showing that all patients with a TOF ratio of 70% could sustain a hand-grip and tongue protrusion [11].


1980: The era of research-based electromyography (EMG) and mechanomyography (MMG) begins.


1981: Viby-Mogensen et al. introduce post tetanic count (PTC) [12].

More About PTC


Post tetanic count (PTC) measures deep neuromuscular blockade when the response to TOF stimulation disappears and the TOF count is 0. The sequence uses a 5 second, 50 Hz stimulation to mobilize acetylcholine from the reserve (post tetanic facilitation). After the tetanic stimulus, a series of single stimuli are applied, once per second. The number of evoked responses to these single stimuli (PTC) corresponds to the level of block, with fewer responses indicating a deeper level of block.

Screenshot 2024-12-10 at 11.44.52

 

 

1985: Viby-Mogensen et al. report that the train-of-four ratio cannot be estimated using subjective methods. 

More About Quantitative Monitoring


Subjective evaluation of TOF requires the observer to remember the magnitude of the 1st response, ignore the next two, and then compare the 4th to the 1st evoked response. Once the TOF ratio exceeds 0.40, most clinicians cannot reliably detect the presence of fade. Thus, it is impossible to be sure by subjective methods if the TOF ratio is 0.50 or 0.95! [13]

Given this information, it became evident that a commercial quantitative monitor was needed. 

 

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1988: Viby-Mogensen and colleagues describe a device that used accelerometry to measure the acceleration of the thumb in response to ulnar nerve stimulation. As force is proportional to acceleration, it was assumed that acceleromyography (AMG) would correlate with mechanomyography (MMG). The device was also thought to be more user friendly than the cumbersome research devices employing EMG and MMG [14, 15].

1997: Eriksson et al. show that at a TOF <90%, patients are at risk for aspiration due to weakness of upper airway muscles [16]. Consistent with Eriksson's findings, Kopman et al. administer neuromuscular blocking agents to awake volunteers who exhibit clinically significant signs of residual neuromuscular blockade at a TOF ratio of 70% [17]. Consequently, the standard for adequate recovery was increased from 70% to a TOF ratio ≥90%.

2002: TOF Watch using acceleromyography (AMG) technology is introduced.

More About AMG


Over the next decades, and despite the release of “improved” devices including the Mini-Accelograph, Myotest, TOF Guard, TOF Watch, TOF Watch S, TOF Watch SX and Stimpod, accelerometry-based twitch monitoring never became commonplace. Studies begin to emerge suggesting that various AMG devices tend to overestimate recovery compared to the MMG or EMG [18, 19]. 



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2010: Naguib et al. publish survey results that reveal significant confusion within the anesthesiology community regarding muscle relaxants. Authors recommended that professional organizations develop training and official guidelines on best practices for neuromuscular monitoring to help decrease the incidence of residual block [20].

2014: Todd and colleagues at University of Iowa release results following the implementation of a department wide EMG-based quantitative monitoring protocol. Universal monitoring led to a significant reduction in residual paralysis, but achievement took time and required extensive education and provider feedback [21].

2015: FDA approves Bridion (sugammadex) to reverse the effects of neuromuscular blocking drugs [22].

 

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2016: The manufacturer of the TOF Watch announces that it is halting production. Expert reviews of the scientific literature identify significant fundamental flaws in AMG, including the unacceptable overestimation of the TOF ratio and its inability to function effectively with tucked hands (accelerometry depends on the thumb's ability to move freely) [23, 24]. Ironically, the perception of accelerometry as a “user-friendly” alternative to MMG and EMG might have delayed widespread adoption of quantitative monitoring.

2018: Blink Device Company announces launch of TwitchView® Quantitative Train-of-four Monitor utilizing electromyography (EMG) and automated post tetanic count (AutoPTC™)

More About EMG


Electromyography (EMG) measures the electrical activity of a muscle following nerve stimulation. While some studies comparing MMG and EMG have found slight differences, others have found the techniques to be directly comparable [6, 25]. Epstein and Epstein performed an early study comparing MMG to EMG and concluded that EMG was in fact more sensitive than MMG for monitoring neuromuscular blockade [26].  

Now that modern electronics have made it easier to measure and quantify EMG signals in real time, EMG is much easier to use in clinical setting compared to MMG. Placement of the electrodes is straightforward, preload is not necessary, and tucking the arms does not affect results. 

 

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2020: Bowdle reports that the TOF ratio measured with TwitchView®, resembles gold-standard mechanomyography (MMG) [27].

2023: American Society of Anesthesiology releases the practice guidelines for Monitoring and Antagonism of Neuromuscular Blockade. Learn more about implementing the ASA practice guidelines.

Highlights From the ASA Guidelines
  1. When neuromuscular blocking drugs are administered, we recommend against clinical assessment alone to avoid residual blockade due to insensitivity of assessment.
  2. We recommend quantitative monitoring over qualitative assessment to avoid residual blockade. 
  3. When using quantitative monitoring, we recommend confirming a ratio greater than or equal to 0.9 before extubation. 
  4. We recommend using the adductor pollicis muscle for neuromuscular monitoring. 
  5. We recommend against using eye muscles for neuromuscular monitoring [28]. 

 

 

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May 2023: Thilen et al. eliminate residual paralysis using a rocuronium management protocol guided by TwitchView quantitative monitoring [29]:

0% 17% 35% 48%
of patients suffered from residual paralysis. Considerable cost savings possible with the help of quantitative monitoring. of patients spontaneously recovered of patients reversed with neostigmine of patients reversed with sugammadex

 

June 2023: U.S. District Court for the District of New Jersey affirms and validates Merck’s U.S. patent protection for BRIDION® (sugammadex) through at least January 2026 [30].

July 2023: Bowdle et al. conduct a dose-finding study titrating sugammadex in 50 mg increments until a Train-of-Four Ratio (TOFR) of 90% is achieved [31]. 


Highlights From "Silver Bullet" Study
The study reveals that:
  • 87% of patients require less than the recommended dose
  • 13% of patients require more than the recommended dose
  • This demonstrates that quantitative monitoring is essential for confirming adequate reversal. 
  • An accompanying editorial concludes, “[The study] contradicts the widespread belief that simply giving the recommended dose of sugammadex ensures adequate reversal. While we have no objections to these recommended (and Food and Drug Administration–approved) doses, the Bowdle study strongly argues that the recommendations should be combined with careful monitoring…and indicates that clinicians who do not see the necessity for quantitative neuromuscular monitoring when reversing residual block with sugammadex need to rethink their position. 

 

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April 2024: Blink Device Company releases a new line of electrodes, including a redesigned adult electrode featuring slimmer profile.

Coming up in 2025…
Blink Device Company launches TwitchView2®! Leveraging thousands of hours of real-world experience and feedback from early adopters, Blink’s team of engineers, medical scientists, regulatory, and medical device experts refined, retested, and enhanced every aspect of the original TwitchView® System to develop TwitchView2® quantitative train-of-four monitor.

 

Curious how continuous neuromuscular monitoring
can impact your reversal strategy?

 

 

History of TOF Infographic 2b

 

Implementation

With you every step of the way

Our sole focus is advancing the quality and use of quantitative neuromuscular monitors. To enable the success of our hospital partners, we've developed an implementation pathway and multi-part training that we will tailor to your institution’s goals and needs. 

Submit a request to start your customized plan and your regional representative will be in touch shortly. Contact us today!

 

References

1. Morris LE, Schilling EA, Frederickson EL. The use of tensilon with curare and nitrous oxide anesthesia. Anesthesiology 1953; 14:117-25


2.Beecher HK, Todd DP. A study of the deaths associated with anesthesia and surgery. Ann Surg 140:2-35, 1954


3. Christie TH, Churchill-Davidson HC: The St. Thomas's hospital nerve stimulator in the diagnosis of prolonged apnea. Lancet 1:776, 1958


4. Churchill-Davidson HC, Christie TH: The diagnosis of neuromuscular block in man. Br J Anaesth 1959; 31:290-301


5. Churchill-Davidson HC. A portable peripheral nerve stimulator. Anesthesiology 1965; 26:224-6


6. Katz RL. Comparison of electrical and mechanical recording of spontaneous and evoked muscle activity. Anesthesiology 1965; 26:204-211


7. Katz RL. A nerve stimulator for the continuous monitoring of muscle relaxant action. Anesthesiology 1965; 26:832-33


8. Ali HH, Utting JE, Gray TC. Quantitative assessment of residual antidepolarizing Block (Part I). Br J Anaesth 1971; 43:473-7


9. Ali HH, Utting JE, Gray TC. Quantitative assessment of residual antidepolarizing Block (Part II). Br J Anaesth 1971; 43:478-485


10. Ali, H. H., Wilson, R. S., Savarese, J. J., & Kitz, R. J. (1975). The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. British journal of anaesthesia, 47(5), 570–574. 


11.Brand, J. B., Cullen, D. J., Wilson, N. E., & Ali, H. H. (1977). Spontaneous recovery from nondepolarizing neuromuscular blockade: correlation between clinical and evoked responses. Anesthesia and analgesia, 56(1), 55–58. 


12. Viby-Mogensen J, Howardy-Hansen P, Chræmmer-Jørgensen B, Ørding H, Engbæk J, Nielsen A. Posttetanic Count (PTC) A New Method of Evaluating an Intense Nondepolarizing Meeting Abstracts. The Journal of the American Society of Anesthesiologists. 1981; 55(4):458-61.


13. Viby-Mogensen, J., Jensen, N. H., Engbaek, J., Ording, H., Skovgaard, L. T., & Chraemmer-Jørgensen, B. (1985). Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology, 63(4), 440–443. 


14. Viby-Mogensen J, Jensen E, Werner M, Nielsen HK. Measurement of acceleration: a new method of monitoring neuromuscular function. Acta anaesthesiologica scandinavica. 1988 Jan 1;32(1):45-8.


15. Jensen E, Viby-Mogenesen J, Bang U.  The Accelograph: A new neuromuscular transmission monitor.  Acta Anaest Scand; 1988;32-49-52


16. Eriksson, L. I., Sundman, E., Olsson, R., Nilsson, L., Witt, H., Ekberg, O., & Kuylenstierna, R. (1997). Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans . Anesthesiology, 87(5), 1035–1043. 


17. Kopman, A. F., Yee, P. S., & Neuman, G. G. (1997). Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in awake volunteers. Anesthesiology, 86(4), 765–771.


18. Kopman AF, Klewicka MM, Neuman GG. The relationship between acceleromyographic train-of-four fade and single twitch depression. The Journal of the American Society of Anesthesiologists. 2002 Mar 1;96(3):583-7.


19. Loan PB, Paxton LD, Mirakhur RK, Connolly FM, McCoy EP. The TOFGuard neuromuscular transmission monitor. Anaesthesia. 1995;50(8):699-702.


20. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current neuromuscular practice in the United States and Europe. Anesth Analg 2010; 111: 110-119.


21. Todd, Michael M. MD; Hindman, Bradley J. MD; King, Brian J. BA. The Implementation of Quantitative Electromyographic Neuromuscular Monitoring in an Academic Anesthesia Department. Anesthesia & Analgesia 119(2):p 323-331, August 2014. DOI: 10.1213/ANE.0000000000000261


22. Drugs.com. (n.d.). Bridion (sugammadex) history. Retrieved December 5, 2024, from https://www.drugs.com/history/bridion.html


23. Naguib M, Brull SJ, Kopman AF, et al. Consensus Statement on Perioperative Use of Neuromuscular Monitoring. Anesth Analg. 2018;127(1):71-80.


24. Andrew Bowdle, Kelly Michaelsen; Quantitative Twitch Monitoring: What Works Best and How Do We Know?. Anesthesiology 2021; 135:558–561


25. Weber S, Muravchick S. Electrical and mechanical train-of-four responses during depolarizing and nondepolarizing neuromuscular blockade. Anesth Analg 1986; 65(7):771-6


26. Epstein RA, Epstein RM. The electromyogram and the mechanical response of indirectly stimulated muscle in anesthetized man following curarization. Anesthesiology. 1973; 38(3):212-23.


27.Bowdle, A., Bussey, L., Michaelsen, K., Jelacic, S., Nair, B., Togashi, K., & Hulvershorn, J. (2020). A comparison of a prototype electromyograph vs. a mechanomyograph and an acceleromyograph for assessment of neuromuscular blockade. Anaesthesia, 75(2), 187–195.


28. Thilen, S. R., Weigel, W. A., Todd, M. M., Dutton, R. P., Lien, C. A., Grant, S. A., Szokol, J. W., Eriksson, L. I., Yaster, M., Grant, M. D., Agarkar, M., Marbella, A. M., Blanck, J. F., & Domino, K. B. (2023). 2023 American Society of Anesthesiologists Practice Guidelines for monitoring and antagonism of neuromuscular blockade: A report by the American Society of Anesthesiologists Task Force on Neuromuscular Blockade. Anesthesiology, 138(1), 13–41.


29. Thilen, S. R., Sherpa, J. R., James, A. M., Cain, K. C., Treggiari, M. M., & Bhananker, S. M. (2023). Management of Muscle Relaxation With Rocuronium and Reversal With Neostigmine or Sugammadex Guided by Quantitative Neuromuscular Monitoring. Anesthesia & Analgesia 139(3):p 536-544, September 2024.


30. Merck. (n.d.). U.S. District Court for the District of New Jersey rules in favor of Merck in patent infringement lawsuit related to Bridion® (sugammadex). Retrieved November 19, 2024, from https://www.merck.com/news/u-s-district-court-for-the-district-of-new-jersey-rules-in-favor-of-merck-in-patent-infringement-lawsuit-related-to-bridion-sugammadex/

 

31. Bowdle, T. A., Haththotuwegama, K. J., Jelacic, S., Nguyen, S. T., Togashi, K., & Michaelsen, K. E. (2023). A Dose-finding Study of Sugammadex for Reversal of Rocuronium in Cardiac Surgery Patients and Postoperative Monitoring for Recurrent Paralysis. Anesthesiology, 139(1), 6–15.

 

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