Naguib, Mohamed MB, BCh, MSc, FFARCSI, MD*; Lien, Cynthia A. MD†; Aker, John CRNA, MS*; Eliazo, Rudolfo BA†
The depolarizing neuromuscular blocker succinylcholine is a unique drug. Despite the long list of potential and sometimes serious side effects associated with its use (1), succinylcholine has remained, for >50 years, the drug of choice during rapid-sequence induction of anesthesia. It remains popular because of its rapid onset of effect and ultrashort duration of action. Although the characteristics of succinylcholine-induced block appear to be well understood (2,3), other evidence suggests otherwise (4).
When succinylcholine (0.5 to 1.5 mg/kg) is administered to patients with normal butyrylcholinesterase activity, a typical depolarizing neuromuscular block (Phase I) develops. Phase I block is characterized by an absence of fade to train-of-four (TOF) (3) or tetanic stimulation (5) and an absence of posttetanic potentiation (2). This has also been observed in vitro in rat phrenic nerve diaphragm preparations during the so-called initial response of succinylcholine (6). With the administration of large doses of succinylcholine, tachyphylaxis develops (7). As tachyphylaxis develops, the succinylcholine-induced block changes from Phase I (depolarizing) to Phase II. Phase II block has more of the characteristics of a nondepolarizing block in response to monitoring, and fade is seen in response to TOF stimulation (7,8).
Almost 35 yr ago, De Jong and Freund (9) stated that succinylcholine-induced neuromuscular block “. . .presented from the onset with the typical characteristics of a phase II block” and that “. . .phase I block. . . .was never observed even with smallest effective blocking doses of succinylcholine. . . .” They (9), however, had administered succinylcholine after equilibration with halothane (inspired concentration of 0.8%–1.5%) for ≥45 min. The use of halothane may have contributed to their observations (3,10).
In 2001, Naguib (4) noted that after the administration of a single dose of succinylcholine during propofol/narcotic/nitrous oxide/oxygen anesthesia, the recovery of neuromuscular function was characterized by the presence of both fade (to TOF and tetanic stimulation) and sustained posttetanic potentiation. Further, Kim et al. (11) reported that TOF fade occurs during the onset of block induced by small doses (0.05–0.3 mg/kg) of succinylcholine, similar to that seen with nondepolarizing neuromuscular blockers. Uncertainty remains, therefore, about the characterization of succinylcholine-induced neuromuscular block. In this prospective study, conducted in two medical centers, we attempted to confirm the anecdotal observations regarding tetanic and TOF fade and posttetanic potentiation seen after bolus administration of different doses of succinylcholine.
After obtaining IRB approval from both the University of Iowa Hospitals and Clinics and New York Presbyterian Hospital and after obtaining written, informed consent, we studied 100 ASA physical status I patients of both genders (age: mean, 36 yr; 95% confidence interval [CI], 34–38 yr; weight: mean, 75 kg; 95% CI, 72–78 kg; height: mean, 171 cm; 95% CI, 169–173 cm). All patients were scheduled to undergo elective procedures; had no neuromuscular, renal, or hepatic disease; and were not taking any drugs known to interfere with neuromuscular function. Exclusion criteria included patients with a body mass index >30 kg/m2, a history of drug or alcohol abuse, gastroesophageal reflux, hiatus hernia, susceptibility to malignant hyperthermia, or anticipated difficult intubation. An IV infusion of lactated Ringer's solution was started before the induction of anesthesia. Routine monitoring was used, and the central temperature was maintained at >36°C.
All patients received 2 mg of midazolam for pre-medication. After the induction of anesthesia with fentanyl 5–6 μg/kg and propofol 2–2.5 mg/kg, anesthesia was maintained with 70% nitrous oxide in oxygen supplemented with a propofol infusion of 120–180 μg · kg−1 · min−1 and incremental doses of fentanyl as required. The trachea was intubated without the use of neuromuscular blocking drugs. After tracheal intubation, the end-tidal concentrations of nitrous oxide, oxygen, and carbon dioxide were determined continuously. Ventilation was adjusted to maintain normocapnia (end-tidal carbon dioxide partial pressure of 36–40 mm Hg).
Monitoring of neuromuscular block was initiated before the administration of succinylcholine. The ulnar nerve was stimulated supramaximally at the wrist with 0.2-ms square pulses delivered in a TOF sequence at 2 Hz every 12 s by using a peripheral nerve stimulator. To facilitate stabilization of twitch height, a 5-s, 50-Hz tetanus followed by a 2-min stabilization period was used (12). The resultant contraction of the adductor pollicis muscle was recorded with a mechanomyograph. Approximately 200–300 g of resting tension was applied to the thumb. The first twitch (T1) of the TOF was considered the twitch height. The amplitude of T1 in each TOF sequence immediately after the period of stabilization was taken as the control with which all subsequent T1 values were compared.
Patients were randomly allocated to 1 of five groups to receive 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg succinylcholine. Once the twitch response had stabilized, succinylcholine was injected over 5 s into a rapidly flowing IV line. At 10%–20% spontaneous recovery of T1, the mode of stimulation was changed from TOF to 1-Hz single-twitch stimulation followed by a tetanic stimulus (50 Hz) for 5 s. Three seconds later, the single twitch (1 Hz) was applied again for approximately 30 s, followed by TOF stimulation until full recovery of the TOF response (Fig. 1). Thereafter, the study was concluded, and anesthesia was continued as appropriate for surgery.
Data were analyzed for the following: the maximum increase in T1 (percentage of control) after the administration of succinylcholine (twitch augmentation), the relation between T1 and the TOF ratio during the onset of block, maximum depression of T1, time from the end of injection to T1 = 10% (of control), pretetanic TOF ratio, pretetanic twitch height (percentage of control), tetanic fade ratio (the ratio between the lowest to highest tension observed in tetanic response, where a ratio of 1.0 indicates that the tetanic response was sustained without fade and a lower ratio indicates the presence of tetanic fade), the maximum and minimum posttetanic twitch height (percentage of control), post-tetanic TOF ratio, and maximum recovery of TOF ratio.
Data were analyzed with a one-way analysis of variance. Post hoc comparisons were performed with the Tukey Studentized range test. The pretetanic twitch height (percentage of control) and the maximum and minimum posttetanic T1 (percentage of control) were compared by using analysis of variance for repeated measures, and post hoc comparisons were performed with the Tukey-Kramer multiple comparisons test. Least-squares linear regression analysis was used to test for any relationships between the dose of succinylcholine and pretetanic twitch height (percentage of control) to tetanic fade ratio. The 95% CIs for the slope and intercept were calculated. Statistical analyses were performed by using the BMDP statistical package (Release 7.01; University of California Press, Berkeley, CA). Onset data were tested by analysis of covariance to determine whether there were interinstitutional differences in the dose-response relationships. Results were expressed as mean and SD or as 95% CIs, and they were considered significant when P < 0.05.
There were no differences in age, weight, height, or gender distribution among the groups. Two patients were excluded from the study because of technical problems. There were no interinstitutional differences in the data.
Complete (100%) neuromuscular block was noted in 0%, 32%, 89%, 100%, and 100% of patients given 0.1, 0.3, 0.5, 0.75, and 1.0 mg/kg succinylcholine, respectively. Maximum neuromuscular block was significantly less in patients given 0.1 mg/kg succinylcholine than in all other dosing groups. Only 2 patients in the 0.1 mg/kg group had a twitch depression >90% of control tension. As shown in Table 1, twitch augmentation before T1 depression was seen in 6 of 16, 8 of 19, 3 of 18, 2 of 19, and 5 of 26 patients given 0.1, 0.3, 0.5, 0.75, and 1.0 mg/kg succinylcholine, respectively. The average level of twitch augmentation was similar among the groups regardless of the dose of succinylcholine. TOF fade during onset of block was common at all doses of succinylcholine administered. During onset of block, TOF ratios as low as 0.12 were observed. As shown in Figure 2, T1 significantly correlated with the TOF ratio (P < 0.001; r2 = 0.54; slope = 0.0037 [0.0034–0.004]; y intercept = 0.57 [0.54–0.59]).
TOF fade was noted during recovery from succinylcholine-induced block (Table 1) in all dosing groups. There were no differences in the TOF ratio among the dosing groups, and the degree of fade on recovery of neuromuscular function was not related to T1. The TOF ratio during recovery varied from 0.2 to 1.0. Tetanic fade was noted in 1 of 2, 11 of 15, 17 of 18, 16 of 18, and 23 of 26 patients given 0.1, 0.3, 0.5, 0.75, and 1.0 mg/kg succinylcholine, respectively. Pretetanic twitch heights were comparable among the different dosing groups. Tetanic fade ratios were significantly correlated with the pretetanic twitch height (P < 0.001; r2 = 0.233; slope = 0.0138 [0.008–0.019]; y intercept = 0.53 [0.45–0.61]) (Fig. 3). The greater the pretetanic twitch height, the larger the observed tetanic fade ratio. Linear regression showed no correlation between the dose of succinylcholine and tetanic fade ratio (Fig. 4). Consistently after tetanus the twitch response became and remained more than the pretetanic twitch height (P < 0.01). Fade in the TOF response was again observed after the tetanic stimulus. Observed TOF ratios ranged from 0.22 to 1.0, and there were no differences in the posttetanic TOF ratios among the dosing groups.
In this study, neuromuscular block after the administration of a single dose of succinylcholine during propofol/narcotic/nitrous oxide/oxygen anesthesia had some characteristics of Phase II block. Block after succinylcholine administration was characterized by the following: 1) twitch augmentation before twitch depression was seen more frequently in patients given smaller doses (0.1 and 0.3 mg/kg) than in those given larger doses (0.5–1.0 mg/kg) of succinylcholine; 2) TOF fade occurred during the onset of and recovery from the block; 3) tetanic fade varied with the degree of neuromuscular block; and 4) and there was posttetanic potentiation. Almost all patients developed fade in response to TOF and tetanic stimulation. The tetanic fade ratio, although not related to the dose of succinylcholine, was directly related to pretetanic twitch height.
We examined the response to stimulation after several doses of succinylcholine, some of which are too small to be considered useful in the clinical setting. This range of doses was chosen to determine whether a response at one dose was seen only at that dose or whether it was applicable over a wide range of doses. Although the result of tetanic stimulation at any point in recovery could have been studied, we chose to study the results of tetanic stimulation at 10% recovery of neuromuscular function. We chose this study design for a number of reasons. Recovery from succinylcholine-induced neuromuscular block is rapid. Had we waited to apply the tetanic stimulus at 50% or 75% recovery of T1, we may not have been able to quantify the degree of posttetanic potentiation. Furthermore, because recovery would have been more complete, the fade in the TOF after the tetanic stimulus may have been missed.
Succinylcholine acts as an agonist at the postsynaptic (muscular) nicotinic receptors (13). It also acts at the presynaptic (neuronal) nicotinic receptors to reduce the release of acetylcholine (14,15). Neuromuscular block induced by succinylcholine develops during depolarization and continues during repolarization (16). Phase II block after prolonged exposure to succinylcholine has been attributed to open postsynaptic nicotinic receptor channel blockade (13).
Twitch depression and tetanic (or TOF) fade are independent phenomena. Studies with nondepolarizing blockers have demonstrated that when twitch height has returned to baseline, significant degrees of fade in the TOF may still be present (17). Twitch depression is due to block of postsynaptic nicotinic acetylcholine receptors, whereas tetanic (or TOF) fade results from block of presynaptic nicotinic receptors (18,19). Blockage of the presynaptic nicotinic receptors by neuromuscular blockers prevents acetylcholine from being made available to sustain muscle contraction during high-frequency (tetanus or TOF) stimulation. Because the released acetylcholine does not match the demand, fade develops in response to stimulation. In contrast, blockage of the presynaptic muscarinic receptors with muscarinic antagonists reduces acetylcholine release without producing tetanic fade (20).
Both the TOF and tetanic fade noted in this study could be attributed to the prejunctional effect of succinylcholine (14). The presynaptic mechanism could explain both the twitch augmentation (during the onset of block) and fade phenomenon seen in this study and in other reports (11,21). As we observed, Kim et al. (11) reported that the TOF fade exists during the onset of block after the administration of doses ranging from 0.05 to 0.4 mg/kg succinylcholine during thiopental/fentanyl/nitrous oxide anesthesia. Because onset of block cannot be studied in a steady-state situation, some of the fade in the TOF during the onset of neuromuscular block noted in this study may have been due to the study design and the rapid onset of effect of succinylcholine. With the maximal effect of succinylcholine being observed within two minutes of administration, a significant deepening of block may be noted even after two seconds.
The mechanism underlying the sustained recovery observed in twitch response after the tetanic stimulation (posttetanic potentiation) is not known. One possible explanation is that succinylcholine has a low affinity to prejunctional receptors, and repeated post-tetanic stimulation (1 Hz for ≈30 seconds) will eventually result in an increased release of acetylcholine. Rapid spontaneous recovery from succinylcholine-induced block may also have contributed to some degree of posttetanic potentiation. However, repeated high-frequency stimulation (1 Hz) during a partial nondepolarizing block has been noted to result in a progressive reduction in the magnitude of twitch response (22).
The extent of TOF and tetanic fade noted during recovery from succinylcholine in this study was much less than that seen after the administration of a non-depolarizing neuromuscular blocker. During recovery from a mivacurium-induced neuromuscular block, the TOF ratio ranges from 0 to 0.3 at ≈20% recovery of T1 (17). The TOF ratio at an equivalent degree of T1 recovery from succinylcholine block is ≈0.6–0.7 (Fig. 2). At this level of recovery, it is not possible to detect fade clinically because the subjective tactile or visual response to nerve stimulation cannot detect fade if the TOF ratio is >0.4 (23). In addition, a 50-Hz tetanic stimulation given at 10%–20% T1 recovery from a nondepolarizing neuromuscular block results in profound tetanic fade (24) and not the tetanic fade ratios of 0.60–0.70 noted after succinylcholine in this study (Table 1). Further, unlike our observations with succinylcholine, posttetanic potentiation during recovery from nondepolarizing neuromuscular block is not sustained.
The results of this study are in accord with those reported by De Jong and Freund (9), Donati and Bevan (21), and Kim et al. (11). Twitch augmentation after succinylcholine has been described previously (11,21). Patients in all of our study groups exhibited some degree of Phase II block. We observed TOF ratios as small as 0.12 during the onset of succinylcholine-induced block and 0.20 during recovery of neuromuscular function. Our results are at variance with those reported by Ali et al. (3) and Katz and Ryan (5,25). In their original description of TOF stimulation, Ali et al. (3) stated that “the response to the train of four stimuli was ablated by [succinylcholine] but on recovery all four twitches were of equal height when the twitch response reappeared.”
In conclusion, we did not observe the existence of a pure Phase I block with mechanomyography after bolus administration of different doses of succinylcholine that ranged from 0.1 to 1.0 mg/kg. Our study demonstrated that some characteristics of Phase II block are noticeable during onset and recovery from doses of succinylcholine as small as 0.30 mg/kg. The nature of neuromuscular block induced by a single dose of succinylcholine may be even more complex than was appreciated when it was initially studied.
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