Development of an algorithm using clinical tests to avoid post-operative residual neuromuscular block

Use of neuromuscular monitoring together with pharmacological reversal of neuromuscular blocking drugs in the operation room is able to reduce the incidence of residual paralysis in patients arriving in the postoperative care unit (PACU), especially when a quantitative monitoring device is used [1, 2]. Unfortunately, quantitative neuromuscular monitoring is neither available in many operating rooms nor regularly used worldwide [3‐6]. Many anaesthesiology societies do not reinforce quantitative neuromuscular monitoring [7‐9]. Therefore, in everyday practice, anaesthesiologists often prefer simple peripheral nerve stimulators (PNS) to assess fading qualitatively. However if there is no tactile fading in TOF and double burst stimulation a 50% risk of actual TOF ratio < 0.7 remains. Appeals to use quantitative techniques on a routine basis are not heard and lead to more resistance rather than compliance [10‐12]. This dilemma will most likely not change fundamentally in the near future. Therefore, we will continue to see patients with residual neuromuscular block in the PACU.

Neuromuscular monitoring in awake patients has so far not been validated [13]. Rejection of quantitative neuromuscular monitoring in the PACU is, therefore, more understandable than its widespread intraoperative denial. In other words, it cannot be expected that anaesthetists, who do not rely on quantitative neuromuscular monitoring during anaesthesia, change their approach after anaesthesia. Nevertheless, studies investigating postoperative residual paralysis used neuromuscular monitoring in a postoperative setting [14‐18]. Although these studies could demonstrate accordance between acceleromyography (AMG) and clinical signs of muscle weakness, there is no standard diagnostic tool for postoperative residual neuromuscular block [14‐18].

In this multicentre, prospective, double-blinded, assessor controlled study we developed and validated an algorithm of clinical muscle function tests to identify residual paralysis in awake patients after anaesthesia. First, we tested a set of clinical muscle function tests with train-of-four ratio (TOFR) measured simultaneously by calibrated electromyography (EMG) at the adductor pollicis muscle. Second, the battery of tests was reduced to an algorithm, which becomes applicable in a clinical setting. Finally, an uncalibrated AMG, the algorithm, and qualitative tactile neuromuscular monitoring were validated in a separate set of awake patients by comparison with calibrated EMG.

Residual neuromuscular block in awake patients can be validly identified with an uncalibrated AMG. For the first time we could demonstrate that the combination of four muscle function tests, including duration of arm lift, duration of head lift, duration to keep the eyes open, and ability to swallow 20 ml of water, has a discriminative power comparable to the TOFR of an uncalibrated AMG. Based on three of these tests, an algorithm was developed, which is able to identify patients with a TOFR <0.7 and, with restrictions, a TOFR <0.9.

There is no doubt that calibrated, quantitative neuromuscular monitoring is the gold standard to measure neuromuscular function during anaesthesia and before extubation [21]. Intuitively, one may also prefer common quantitative neuromuscular monitoring in the PACU. In awakening or awake patients after anaesthesia, however, there is no evidence about its quality irrespectively its complex applicability [11, 13]. Nevertheless, the risk to overlook residual or reoccurrence of neuromuscular block after anaesthesia, i.e. in the PACU, necessitates a valid tool for differential diagnostic reasons [22, 23]. This is undergirded by the fact that even with the use of sugammadex without neuromuscular monitoring TOFR in the PACU still remains less than 0.9 in almost 9.4% [24].

The number of and the reasons for excluded patients in this study demonstrate the complexity of any neuromuscular monitoring technique in awake patients, even when continued after anaesthesia. All mandatory measures were applied to guarantee stable measurements of EMG in order to serve as reference method [19]. In addition, we performed the measurements during a 30 min extended stay in the operating room in order to reduce transport related failures. Nevertheless, we were not able to continue EMG much less to reliably start AMG monitoring in 26 patients (13.0%). In this cohort of alert, orientated and cooperative patients, the clinical assessment could not be completed in 4.5% of the patients only. The most difficult test to be carried out was the swallowing test.

In the patients, in whom the technical problems could be controlled, the AMG proved to reproduce the calibrated EMG in the best way. This is even more remarkable, since we mimicked the clinical conditions of a PACU tool, which cannot be calibrated before relaxation as a matter of principle. AMG, however, overestimated the TOFR measured by EMG. This well-known problem is responsible for the risk to overlook a TOFR <0.9 as well as a TOFR <0.7 with AMG (Fig. 6) [25]. Based on the prevalence reported by Debaene et al., Cammu et al., or Murphy et al. an average of 3% – 5% patients must be expected to have a TOFR <0.9, when AMG indicates a TOFR ≥0.9, and, more important, up to 1.6% would be at risk to have a TOFR <0.7, when AMG indicates a TOFR ≥0.7 (Fig. 6) [15, 18, 26]. Accordingly, we recommend increasing the requested level of TOFR recovery when using AMG in awake patients analogously to anaesthetised patients [27, 28].

Tactile neuromuscular monitoring cannot reveal a residual neuromuscular block with a TOFR between 0.4 and 0.9 in anaesthetised patients [29]. In our study, this missing discriminative power of tactile evaluation was confirmed in awake patients. As expected, tactile fading in the TOF-stimulation pattern is neither able to identify a TOFR <0.9 nor a TOFR <0.7 in awake patients (Fig. 6).

Studies investigating residual paralysis found a lack of accordance between individual muscle function tests and uncalibrated AMG monitoring [14, 15]. We confirmed these findings demonstrating that single tests reproduced the well-known varying sensitivity of muscles at arm, neck, pharynx, and eyes (Fig. 3) [30‐33]. Therefore, we used CART to create a clinically practicable algorithm based on the muscle function tests. CART splits the entire sample into two subgroups out of all possible scores searching for the best separation [20]. As the resulting subgroups are analysed in the same way independently until either no significant split could be performed or the sample became too small, a hierarchical model is generated. The result of this modelling has the great advantage of easy applicability without any calculations or technical measurements, simply by logically combing the assessments. Therefore, minor lack of discriminative power may be acceptable, because the clinical practicability effectively increases.

The upper airway function played a key role, when the level of acceptable TOFR recovery was defined to be 0.9 based on a number of sophisticated studies in volunteers [32, 34‐36]. After a successfully performed 5 s arm and a 5 s head lift (node 1, node 7), expectedly, the simplistic test to swallow 20 ml water was not able to discriminate between TOFR <0.9 and TOFR >0.9 alone. Nevertheless, the swallowing test contributed to the algorithm exactly at this TOFR (node 9, Fig. 4).

The high sensitivity (100%) of the algorithm to identify patients with severe residual paralysis (TOFR <0.7) may protect affected patients in the PACU to be overlooked, independent how many patients actually have a TOFR <0.7 (Fig. 6). Since data on respiratory failure support the notion that TOFR <0.7 indicates patients, who are at high and acute risk, the algorithm seems to be an improvement in terms of safety, identifying severe residual paralysis [2].

The high sensitivity of the algorithm, however, also implies the risk to overestimate residual neuromuscular block and therefore provoke overtreatment with its immanent side effects. High dose cholinesterase inhibitors like neostigmine applicated at minimal levels of neuromuscular block, e.g. may induce nausea and vomiting, increase airway secretion, and may paradoxically impair the upper airway muscle function [37, 38].

Residual block with TOFR <0.3 should be recognised before extubation even without any neuromuscular monitoring. But neither pharmacological reversal with neostigmine nor with sugammadex based on non-systematic clinical signs of muscle weakness are able to avoid PORC [39]. It was not our aim to provoke extubation at such deep levels. The members of the study staff, however, routinely apply quantitative neuromuscular monitoring when paralyzing their patients and, therefore, were less experienced to work without it. Nevertheless, no patient was harmed by one of the typical complications of a residual block. Although there was a potential risk of pulmonary aspiration using the swallowing test (20 ml of water), we observed no makro aspiration. Mikro aspiration could not be excluded clinically. This might be due to the short assessment period before reversal with 40 μg/kg neostigmine, the thorough care taking by the study staff expecting patients with a residual block, but also the patients’ preoperative information that such a scenario might happen.

There are limitations to the present investigation. First, the algorithm was developed in a well-defined group of patients (ASA 1, 2) without organ dysfunction. Second, the relatively young study population (18–65 years) was scheduled just for elective, low risk, surgical procedures. Third, just short-acting anesthetic medication (desflurane, remifentanil) was used, enabling sufficient alertness and cooperation after extubation for the clinical assessment. Fourth, swallowing of 20 ml water as a part of the algorithm might provoke aspiration in patients with residual paralysis.

We developed and verified tools for the PACU to identify patients with residual neuromuscular block. AMG, even when used uncalibrated in awakening patients, proved to identify a residual neuromuscular block. An algorithm based on muscle function tests is also able to indicate residual neuromuscular blocks with high sensitivity for a TOFR <0.7. This tool might reduce the risk to overlook severe residual neuromuscular block in the PACU of institutions, in which only qualitative neuromuscular monitoring with PNS is used.

Further clinical studies are necessary to test this muscle function algorithm in other populations (ASA 3–4, age > 65 years) and varying clinical settings.