Relax, but stay Vigilant. What Impact Relaxants can have on Patient Safety?

Relaxants (or, more correctly, neuromuscular blocking agents; NMBAs) are seldom used in veterinary medicine. A recent survey amongst veterinary anesthesia providers showed that most of us use these agents in less than 10% of our cases (1). When agents are used so infrequently, our ability to gain experience, learn their behavior, and answer important question through research, moves slowly. Lack of familiarity with agents adds to the intrinsic risks that the drugs (or techniques) bring to our practice. Despite infrequent use, relaxants are a common part of the anesthetic management for selected procedures, such as ophthalmologic surgery. In some cases, anesthetists incorporate a NMBA as part of balanced anesthesia in animals at increased risk for morbidity or mortality. Hence, even if relaxants are not part of everyday veterinary practice, knowledge about their potential risks and how to minimize them is of importance, especially when these drugs are used in fragile patients.


Relaxants interrupt the transmission between a motor nerve and a skeletal muscle, hence their correct denomination of NMBA. They do not provide any degree of sedation or analgesia; those effects, must be achieved by different means. They produce profound relaxation of the skeletal musculature (resulting in apnea), which may be beneficial in some circumstances. The first inherent risk when using NMBAs is the inadequate provision of hypnosis or analgesia. The risk of awareness under anesthesia in people increases when relaxants are used (2, 3). No such data are available for our patients, but common sense dictates that using drugs that prevent movement in response to stimulation will likely hamper our ability to recognize insufficient depth of anesthesia.

The second inherent risk with relaxants (second in chronological order, not in order of importance or frequency), is the presence of partial block (weakness) that may go unrecognized at recovery. Residual neuromuscular block is a common complication associated with the use of NMBAs. Several studies have identified incidences between 30-50% for this complication in people (4). The consequences of residual block range from mild discomfort to severe respiratory events. In particular, increased risk of aspiration and poor respiratory response to hypoxia have been identified in people with mild residual paralysis (5, 6).


Unsurprisingly, vigilance can help, and the incidence of residual paralysis is greatly minimized through monitoring. Neuromuscular monitoring consists of the stimulation of a motor nerve and the evaluation of the muscular contraction that is elicited; it is neuromuscular transmission what we evaluate. Effective monitoring of neuromuscular function requires a peripheral nerve stimulator (PNS). Relying on passage of time and clearance of NMBAs, or simply observing the animal’s ability to breathe or generate spontaneous movements at the end of anesthesia, are not reliable methods for monitoring. The situation is made more complex by the fact that not all muscles paralyze and recover at the same rate (in fact, potency of NMBAs varies between muscle groups). As a result, dogs regain their ability to breathe relatively early during the offset phase of neuromuscular block. Thus, normal spontaneous ventilation is restored when substantial residual weakness is still present in other muscles (7). Therefore, ventilation (even if measured objectively by a spirometer) is unlikely to represent the status of other muscles and should not be used as a surrogate for neuromuscular monitoring with a PNS.


A PNS is therefore a better way to test neuromuscular transmission; the nerve is stimulated and the muscular response assessed. Stimulation should be performed in most cases with supramaximal current, so that all muscle fibers can be recruited. The impulse should be short (0.1-0.3 msec); short pulses are more likely to stimulate the nerve and not the muscle directly. Direct muscle stimulation bypasses the neuromuscular junction and defeats our purpose. Nerves commonly used for monitoring include the ulnar nerve (medial elbow) and the peroneal nerve (lateral thigh). From the many patterns available to stimulate nerves, the train-of-four (TOF) is the most commonly used. With TOF, the nerve is stimulated with the same current, four times in two seconds. In the absence of neuromuscular block, four muscle twitches of identical magnitude are produced. Partial block results in a progressive decay during TOF. This fade, is a sensitive indicator of incomplete recovery from NMBA. The degree of fade can be quantified by comparing the magnitude of the last (fourth) twitch of the train to the magnitude of the first one; this is the TOF ratio (T4:T1) (Figure 1).


Figure 1: Representation of the train-of-four without neuromuscular block, and with partial neuromuscular block. Fade can be observed during partial block. Note that the TOF ratio may be > 1.0 in the absence of NMBA, as shown in the first train. Recovery from neuromuscular block occurs progressively in the opposite direction.

The video below shows a TOF being applied to a dog. When the differences between T4 and T1 are quite substantial, fade can be detected simply by observing the responses. However, small differences between T4 and T1 are difficult to detect with our senses. In this example, the TOF ratio was 0.7. The probability of detecting a TOF ratio of 0.7 by observation of the responses is 50%, as good as flipping a coin (8). In humans, a TOF ratio of 0.7 can result in aspiration and/or hypoxia. In dogs, this level of partial block measured at the limbs is associated with impaired laryngeal function (9).


Video 1: Train-of-four stimulation in a dog.

Measuring (instead of simply observing) the responses increases the safety of NMBAs in anesthetic practice. The most commonly used technique is acceleromyography (AMG), which quantifies the acceleration of the paw during an evoked twitch. Quantifying the TOF ratio is necessary to identify shallow residual block that could still affect the function of some muscles. It is well established that the incidence of residual block, and its associated negative consequences, are reduced when AMG is being used (10, 11).


However, it is possible that even AMG may not remove all of the risks of residual block. A limitation of neuromuscular monitoring is that neuromuscular transmission is usually only assessed at one site and extrapolated to the entire animal. However, as mentioned above, not all muscles paralyze and recover at the same rate. Ideally, the muscle being evaluated should be the most sensitive to detect partial block; that is, that nerve-muscle unit should recover last. In dogs, laryngeal muscles (at least some of them) recover later than those muscles of the limbs commonly used for neuromuscular monitoring. For example, one study found partial block at the larynx of anesthetized dogs when the TOF ratio measured at the limb had recovered to 0.9 (12) (Figure 2). It took 12 minutes longer for the larynx to recover to the same TOF ratio as the limb. In one animal (out of six), almost 20 minutes were necessary. Even a few minutes with a dysfunctional larynx is a long time in an animal that has just been extubated.


Figure 2: Recovery of the train-of-four ratio (TOFR) measured with electromyography (EMG) at a pelvic limb (circles) and the larynx (triangles) in an anesthetized dog. Note that when the TOF ratio reached 0.9 at the limb, substantial block was still present at the larynx. Adapted from Sakai DM. et al, Vet Anaesth Analg, 2017; 44: 246-253).

The bad news don’t stop there. Routine administration of reversal agents (reverse everyone) does not guarantee that residual block will ever occur, at least when anticholinesterase inhibitor agents, such as neostigmine, are used (13). This situation might become more favorable as selective relaxant binding agents, such as sugammadex (14), are more widely available. In the meantime, judicious dosing of relaxants (avoiding deep block towards the end of the procedure), objective monitoring (such as AMG), and an understanding of neuromuscular pharmacology, are likely the best weapons at our disposal to avoid residual block and make the practice of relaxing patients as safe as possible.


Manuel Martin-Flores DVM, Diplomate ACVAA

Associate Professor, Anesthesiology and Pain Management

College of Veterinary Medicine

Cornell University


Daniel M Sakai DVM, Diplomate ACVAA

Assistant Professor, Anesthesiology

Department of Small Animal Medicine and Surgery

University of Georgia


 

1. Martin-Flores M, Sakai DM, Campoy L, Gleed RD. Survey of how different groups of veterinarians manage the use of neuromuscular blocking agents in anesthetized dogs. Vet Anaesth Analg. 2018.

2. Deis AS, Schnetz MP, Ibinson JW, Vogt KM. Retrospective analysis of cases of intraoperative awareness in a large multi-hospital health system reported in the early postoperative period. BMC Anesthesiol. 2020;20(1):62.

3. Pollard RJ, Coyle JP, Gilbert RL, Beck JE. Intraoperative awareness in a regional medical system: a review of 3 years' data. Anesthesiology. 2007;106(2):269-74.

4. Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva anestesiologica. 2006;72(3):97-109.

5. Eriksson LI, Lennmarken C, Wyon N, Johnson A. Attenuated ventilatory response to hypoxaemia at vecuronium-induced partial neuromuscular block. Acta Anaesthesiologica Scandinavica. 1992;36(7):710-5.

6. Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology. 1997;87(5):1035-43.

7. Martin-Flores M, Sakai DM, Campoy L, Gleed RD. Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade. Vet Anaesth Analg. 2014;41(3):269-77.

8. Martin-Flores M, Sakai DM, Tseng CT, Gleed RD, Campoy L. Can we see fade? A survey of anesthesia providers and our ability to detect partial neuromuscular block in dogs. Vet Anaesth Analg. 2019;46(2):182-7.

9. Tseng CT, Sakai DM, Libin M, Mostowy M, Cheetham J, Campoy L, et al. Partial neuromuscular block impairs arytenoid abduction during hypercarbic challenge in anesthetized dogs. Vet Anaesth Analg. 2017;44(5):1049-56.

10. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS, et al. Intraoperative acceleromyographic monitoring reduces the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit. Anesthesiology. 2008;109(3):389-98.

11. Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Marymont JH, Vender JS, et al. Intraoperative acceleromyography monitoring reduces symptoms of muscle weakness and improves quality of recovery in the early postoperative period. Anesthesiology. 2011;115(5):946-54.

12. Sakai DM, Martin-Flores M, Romano M, Tseng CT, Campoy L, Gleed RD, et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs. Vet Anaesth Analg. 2017;44(2):246-53.

13. Thilen SR, Ng IC, Cain KC, Treggiari MM, Bhananker SM. Management of rocuronium neuromuscular block using a protocol for qualitative monitoring and reversal with neostigmine. Br J Anaesth. 2018;121(2):367-77.

14.Mosing M, Auer U, West E, Jones RS, Hunter JM. Reversal of profound rocuronium or vecuronium-induced neuromuscular block with sugammadex in isoflurane-anaesthetised dogs. Vet J. 2012;192(3):467-71.



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