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NDNMB reversal: TOF ratio

Overview of NDNMB Drugs

Nondepolarizing neuromuscular blocking drugs (NDNMBD) in recent use include mivacurium, atracurium, cisatracurium, vecuronium, rocuronium and pancuronium. These muscle relaxants bind ACh receptors in the neuromuscular junction but are incapable of inducing ion channel opening, functioning as competitive antagonists. (1)

Reversal of NDNMB Drugs

Mivacurium is unique amongst NDNMBDs in terms of its reversal as it is metabolized by plasma cholinesterase. The remainder of NDNMBDs are dependent on unbinding from the receptor, redistribution, and excretion; or administration of a cholinesterase inhibitor to increase junctional ACh concentration to overcome its effect. Alternatively, vecuronium and rocuronium can be reversed by sugammadex which selectively binds the drug. (1)

Peripheral Nerve Stimulation and Train-of-four ratio

Peripheral nerve stimulators can be used at the time of reversal to determine return of neuromuscular function. Four common patterns of stimulation are in use including tetany, single twitch, double-burst stimulation and train-of-four (TOF). TOF is considered to be the standard for monitoring a patient’s neuromuscular function perioperatively. TOF consists of four 2-Hz stimulation applied to a peripheral nerve and monitored for corresponding muscle contraction (See Fig 1). The response to the four twitches is quantified with a comparison of the first and last twitch. (1,2) A fourth twitch response that is equal to or greater than the first would be a TOF ratio of equal or greater than 1 (zero fade), indicating equal or greater response contraction to subsequent stimulation. A TOF ratio of less than 0.9 indicates postresidual block and a TOF ratio of less than 0.7 indicates persistent neuromuscular blockade. (1)

Limitations TOF Ratio Monitoring

Determination of TOF ratio (first twitch compared to last) by visual or tactile has been shown to unreliable in a TOF ratio range of 0.4 to 0.9. The use of quantitative TOF monitoring with an accelerometer can significantly improve detection of residual paralysis. (2)

TOF Ratio and Reversal Agent Administration

The use of neostigmine as a reversal agent is only recommended once the 4th twitch (TOF count = 4) in the TOF is detectable (See Fig 1). However, even with a 4th twitch present the ability of neostigmine to produce an adequate reversal (TOF ratio >0.9) is not guaranteed. When giving neostigmine with only one twitch present, the odds of achieving adequate reversal is zero (2). The odds of achieving adequate reversal improves greatly with the return of subsequent TOF counts. Patient reversed with neostigmine at lower TOF counts may display no apparent fade after neostigmine reversal but cannot be confirmed without quantitative monitoring. (2)

Neuromuscular monitoring. PTC, post tetanic count; TOF, train of four. (Available via Creative Commons License)

Neuromuscular monitoring. PTC, post tetanic count; TOF, train of four. (Available via Creative Commons License)


  1. Thilen SR, Bhananker SM. Qualitative Neuromuscular Monitoring: How to Optimize the Use of a Peripheral Nerve Stimulator to Reduce the Risk of Residual Neuromuscular Blockade. Curr Anesthesiol Rep. 2016;6:164-169. doi:10.1007/s40140-016-0155-8 . Link

Other References

  1. Clar DT, Liu M. Non-depolarizing Neuromuscular Blockers. [Updated 2021 Feb 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Link