Improving the Design of Muscle Relaxant StudiesStabilization Period and Tetanic Recruitment

George C. Lee; Shuba Iyengar; Janos Szenohradszky; James E. Caldwell; Peter M. C. Wright; Ronald Brown; Marie Lau; Andrew Luks; Dennis M. Fisher

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Clinical Science | January 1997

Improving the Design of Muscle Relaxant Studies: Stabilization Period and Tetanic Recruitment

George C. Lee; Shuba Iyengar; Janos Szenohradszky, MD; James E. Caldwell, MB, ChB; Peter M. C. Wright, MD; et al Ronald Brown, BS; Marie Lau, BS; Andrew Luks, BA, MA; Dennis M. Fisher, MD

Author Notes

Article Information

Anesthesiology 1 1997, Vol.86, 48-54. doi:

The magnitude and time course of paralysis induced by muscle relaxants typically vary greatly within and between studies. Recently, McCoy et al. [1] suggested that some of this variability might be explained by the duration of ulnar nerve stimulation before muscle relaxants are administered. They observed that a 1- to 5-min period of stimulation before muscle relaxants are administered (stabilization period) was associated with both a more rapid onset and a clinical duration (time from drug administration to 25% recovery) that was one third less than with a 20-min stabilization period. Because some investigators allow only a 1- to 3-min stabilization period, [2,3] whereas we typically stimulate for more than 20 min before drug administration, we speculate that these differences in study design may, at least partially, explain some of the variability in the findings of studies. In the present study, we extended McCoy et al.'s design in several ways. First, we showed that the neuromuscular response of both arms is similar in time course and magnitude, thereby permitting each participant to act as his or her own control in the remaining studies. In the remaining studies, we used a stabilization period of 20 min in one extremity and 2 min in the other to examine the effects of different periods of predrug stimulation on recovery times. In addition, we tested whether giving a brief (2 s or 5 s) tetanus when stimulation was initiated would facilitate stabilization. Finally, whereas McCoy et al. referenced clinical duration to twitch tension before muscle relaxants were administered, we reference clinical duration to both predrug twitch tension and to the plateau in twitch tension at recovery. We reference clinical duration in the extremity with 2-min predrug stimulation to the plateau at recovery to mimic those investigators who use brief stabilization periods and then reference clinical duration to twitch tension at recovery rather than to the value before drug administration.

Methods

After obtaining approval from our Committee on Human Research, we obtained informed consent from six right-hand-dominant volunteers (classified as American Society of Anesthesiologists [ASA] physical status 1) who were not undergoing surgery and from 20 patients (ASA physical status 1 or 2) undergoing various elective peripheral surgical procedures. Volunteers and patients were excluded if they had a history of neuromuscular disease or hepatic or renal insufficiency. No volunteer or patient received anticonvulsants or aminoglycoside or polypeptide antibiotics before or during anesthesia. Volunteers ranged from 22–35 yr old and patients from 17–55 yr old.

Anesthesia was induced with 5 micro gram/kg fentanyl and 2–2.5 mg/kg propofol, and tracheal intubation was accomplished without administering muscle relaxants. For volunteers, anesthesia was maintained with propofol, 150–200 micro gram [centered dot] kg sup -1 [centered dot] min sup -1. For patients, anesthesia was maintained with 60% nitrous oxide and isoflurane (end-tidal concentration to 0.8%); isoflurane concentrations were stable for more than 15 min before muscle relaxants were administered and were not changed during the rest of the study. Ventilation was controlled to maintain end-tidal P^CO²at 30–35 mmHg. Esophageal temperature was maintained at > 36 degrees Celsius with forced-air warming devices. Blood pressure was measured in the leg.

After induction of anesthesia, each upper extremity was taped to a padded grip and the thumb was abducted. Tension of the adductor pollicis muscle was measured using a force transducer (Myotrace, Houston, TX) calibrated in grams. The force signal was amplified (DC Bridge Signal Conditioner; Gould Electronics, Valley View, OH), digitized (NB-MIO-16; National Instruments, Austin, TX) on a Macintosh computer, and displayed (LabView, National Instruments). Values were recorded to a spreadsheet (Microsoft Excel, Redmond, WA). Resting preload was adjusted until equal (< 10% difference) in the two extremities, with the goal of maintaining constant values of 200–400 g.

When preload was stable for more than 10 min, supramaximal square-wave train-of-four stimuli, lasting 0.2 ms, were administered at 2 Hz every 12 s to the ulnar nerve via needle electrodes at the wrist. The magnitude of the first component (T1) of the train-of-four was determined.

Stimulation patterns differed in the four phases of the study, as follows.

Phase 1: Control Studies

In six volunteers, stimulation of both ulnar nerves was started simultaneously and adjusted to supramaximal (the nerve stimulator was set to its lowest output for one train-of-four, its output was increased after each train-of-four until further increases produced no further increment in twitch tension, then output of the nerve stimulator was increased 20% and not adjusted again). Vecuronium, 30 micro gram/kg, was given after more than 30 min of stimulation; the value for twitch tension immediately before vecuronium was defined as the predrug control value in this and all subsequent phases of the study. Train-of-four stimulation was continued and twitch tension recorded until a plateau was achieved for more than 15 min (recovery control). These studies showed that the response of the two adductor pollicis muscles was nearly identical (see Results), thereby permitting paired comparisons among participants for phases 2–4.

Phase 2: No Tetanus

In six patients, at -20 min (i.e., 20 min before drug administration), nerve stimulation was started at one ulnar nerve (first extremity, Figure 1). Supramaximal stimulation was rapidly attained, typically within 0.6–1.0 min; twitch tension at this time was defined as the postsupramaximal value. No stimulation was applied to the other ulnar nerve (second extremity). At -2 min, the identical stimulation sequence was applied to the second extremity. At 0 min, 30 micro gram/kg vecuronium was given.

Figure 1. Time course of nerve stimulation in the two extremities is shown for phases 2–4. Train-of-four stimulation was initiated in one extremity at -20 (i.e., 20 min before drug was administered), and supramaximal response was established in 0.6–1 min. At -2 min, train-of-four stimulation was initiated in the second extremity preceded by no tetanus (phase 2), a 2-s tetanus (phase 3), or a 5-s tetanus (phase 4); immediately thereafter, a supramaximal response was attained. Vecuronium, 30 micro gram/kg, was given at time 0.

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Phase 3: Two-second Tetanus

In six patients, the stimulation sequence was identical to that in phase 2 except that, at -2 min, stimulation in the second extremity was initiated with a single 2-s 50-Hz tetanus at full output of the nerve stimulator; immediately thereafter, supramaximal stimulation was attained. Twitch tension immediately after attaining supramaximal stimulation was defined as the postsupramaximal value.

Phase 4: Five-second Tetanus

In eight patients, the stimulation sequence was identical to that in phase 3 except that, at -2 min, the tetanic stimulus lasted 5 s rather than 2 s.

The following values were determined and compared between extremities:

1. predrug control twitch tension as a percentage of postsupramaximal twitch tension (phases 2–4 only)

2. time to and magnitude (referenced to predrug control) of peak twitch depression or time to obliteration of twitch (all phases) and time to 90% twitch depression (referenced to predrug control, phases 2–4 only)

3. recovery control twitch tension as a percentage of predrug control (all phases)

Time to 10%, 25%, and 90% recovery of twitch tension were referenced to two indices-predrug control and recovery control. In phase 1, comparisons were made between

1. left arm versus right, both referenced to predrug control

2. left arm versus right, both referenced to recovery control

3. left arm referenced to predrug control versus the same arm referenced to recovery control

4. right arm referenced to predrug control versus the same arm referenced to recovery control

5. left arm referenced to predrug control versus the right arm referenced to recovery control

6. left arm referenced to recovery control versus the right arm referenced to predrug control

In phases 2–4, comparisons were made between

1. the extremity with 20-min prestimulation versus the extremity with 2-min prestimulation, both referenced to predrug control

2. the extremity with 20-min prestimulation referenced to predrug control versus the extremity with 2-min prestimulation referenced to recovery control

3. the extremity with 2-min prestimulation referenced to predrug control versus the same extremity referenced to recovery control

4. the extremity with 20-min prestimulation referenced to predrug control versus the same extremity referenced to recovery control.

Values are reported as mean +/- SD. All comparisons were performed using one-sample or paired-sample Student's t tests or their nonparametric equivalents. Differences were considered significant at P <0.05 (adjusted for multiple comparisons).

Results

Phase 1: Control Studies

Time to and magnitude of peak block were similar for the two extremities (Table 1). Because five of six volunteers developed less than 90% twitch depression, time to 90% twitch depression and 10% recovery of twitch tension were not determined. Recovery control did not differ from predrug control twitch tension for either extremity. Time to 25% recovery and to 75% recovery were similar when referenced to predrug and recovery control values and for both extremities.

Table 1. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom Both Extremities Were Stimulated Identically (Phase 1)

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Phase 2: No Tetanus

The extremity with 20-min prestimulation showed a marked increase in twitch tension during that period (Figure 2, Table 2); the extremity with 2-min prestimulation showed less increase in twitch tension. Time to 90% and to peak block were more rapid in the extremity with 20-min prestimulation; there was no difference between extremities in the magnitude of peak effect (most patients became completely paralyzed). For the extremity with 20-min prestimulation, predrug control and recovery control twitch tensions did not differ. For the extremity with 2-min prestimulation, recovery control exceeded predrug control. Times to 10%, 25%, and 75% recovery were longer for the extremity with 20-min prestimulation compared with 2-min prestimulation (referenced to either pre-drug or to recovery control). There was a small difference (0.5 +/- 0.4 min) in 25% recovery time for the extremity with 20-min prestimulation when referenced to predrug versus recovery control. For the extremity with 2-min prestimulation, time to 75% recovery was longer when referenced to recovery control than when referenced to predrug control.

Figure 2. Time course of neuromuscular function in one extremity in a representative patient from phase 2. At -20 min (i.e., 20 min before drug was administered), train-of-four stimulation to the ulnar nerve was started; stimulator output was constant after -19 min. At time 0, 30 micro gram/kg vecuronium was given. During 20-min predrug stimulation, twitch tension increased markedly.

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Table 2. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom Duration of Predrug Stimulation Differed between Extremities and No Tetanus Was Administered (Phase 2)

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Phase 3: Two-second Tetanus

The extremity with 20-min prestimulation showed a marked increase in twitch tension during that 20-min period and recovery control twitch tension was less than predrug control twitch tension (Table 3). In contrast, the extremity with 2-min prestimulation (with 2-s tetanus) showed no increase in twitch tension during that 2-min period, and recovery control twitch tension was similar to predrug control twitch tension. Magnitude of peak block (most patients became completely paralyzed) and time to 90% twitch depression and to peak block were similar for the two extremities. Time to 10% recovery was similar for the two extremities and did not differ when referenced to either predrug control or recovery control. For the extremity with 20-min prestimulation, times to 25% and 75% recovery were briefer when referenced to recovery control than when referenced to predrug control.

Table 3. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom a 2-s Tetanus Was Administered to One Extremity (Phase 3)

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Phase 4: Five-second Tetanus

The extremity with 20-min prestimulation showed a marked increase in twitch tension during that 20-min period, and recovery control twitch tension was similar to predrug control twitch tension (Table 4). In contrast, the extremity with 2-min prestimulation (with 5-s tetanus) showed no increase in twitch tension during that 2-min period, and recovery control twitch tension was similar to predrug control twitch tension. Magnitude of peak block (most patients became completely paralyzed) and time to 90% twitch depression and to peak block were similar for the two extremities. Time to 10%, 25%, and 75% recovery were similar for the two extremities and did not differ when referenced to either predrug control or recovery control.

Table 4. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom a 5-s Tetanus Was Administered to One Extremity (Phase 4)

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Discussion

The magnitude and time course of paralysis induced by a muscle relaxant often vary tremendously among studies. For example, two studies examined time to 25% recovery of twitch tension after 50 micro gram/kg doxacurium was given to adults anesthetized with thiopental, nitrous oxide, and opioids: Basta et al. [4] reported a value of 83 +/- 11 min, whereas Murray et al. [5] reported a value of 123 +/- 26 min. We were interested in determining whether some of the variability between studies could be explained as a function of study design. For example, did the method by which investigators stimulated the ulnar nerve (details of which are rarely provided) influence the neuromuscular response? McCoy et al. [1] recently suggested that stimulation patterns do influence the response to muscle relaxants. In an unpaired study, they administered one of three muscle relaxants to patients anesthetized with nitrous oxide and fentanyl. The stabilization period ranged from 1–20 min and no tetanic stimuli were given. They observed that onset was more rapid and that recovery of twitch tension to 25% of the predrug control value was slower after longer stimulation. They speculated that this more rapid onset and longer clinical duration resulted because nerve stimulation increased blood flow, and therefore delivery of muscle relaxant, to the neuromuscular junction.

Our study offers no insight into why onset and clinical duration varying with duration of prestimulation. However, we note that during the 20-min stabilization period, twitch tension increases progressively and that this increase slows after 10 min (Figure 2). If a muscle relaxant is administered before this increase plateaus, twitch tension might eventually recover to a value approaching that which would have been attained with a longer stabilization period. This is supported by our finding in phase 2 that recovery control for the extremity that received only 2 min of prestimulation was 111 +/- 10% of its predrug control. Thus, with brief periods of predrug stimulation, 75% recovery was shorter if referenced to predrug control (similar to that in McCoy et al.'s study) than if referenced to recovery control (as in some other studies). Our findings are consistent with McCoy et al.'s and suggest that a brief stabilization period yields values for onset and recovery different from those with a longer period of stabilization.

Recently a consensus panel proposed standards for nerve stimulation and monitoring of neuromuscular function during studies of muscle relaxants. [6] Viby-Mogensen et al. [6] recommend that a stable control response be established for 10 min before a muscle relaxant is given. Our results support this recommendation if no tetanic stimuli are given when stimulation is initiated. In addition, Viby-Mogensen et al. conclude that “all data recorded during recovery from neuromuscular block should be ‘normalized’ to the final T¹value.” This recommendation may hamper those investigators who administer additional muscle relaxants before recovery is complete. If the mode and duration of nerve stimulation results in predrug control that does not differ from recovery control, then either could be used interchangeably. In phase 1 and in the extremity with 20-min prestimulation in phase 4, final control equaled predrug control. However, in phase 3, recovery control of the extremity with 20-min prestimulation averaged less than predrug control and, in phase 2, recovery control was less than 95% of predrug control in five of six participants. A decrement of twitch tension over time (20% during 2 h) in the absence of muscle relaxants was reported in cats anesthetized with pentobarbital, alpha-chloralose, and urethan. [7] However, two studies in humans, one during opioid anesthesia, the other during isoflurane anesthesia, failed to demonstrate time-dependent changes in twitch tension. [8,9] Therefore, we cannot explain the small decrement in twitch tension seen in phases 2 and 3. Fortunately, that decrement in recovery twitch tension was small so that recovery times differed only slightly (although sometimes statistically), depending on the control value to which they were referenced.

Because of time pressures in performing clinical research, a 20-min stabilization period may be prohibitive. This presumably explains why many investigators choose a brief stabilization period, such as 1–3 min, and claim that twitch tension stabilized during that period. However, our results (Figure 2) suggest that in the absence of a tetanic stimulation, a longer period is needed to obtain a stable baseline signal. To facilitate stabilization of twitch tension, we administered tetanic stimuli lasting either 2 s or 5 s. We hypothesized that whatever mechanism increased twitch tension during the 20-min stabilization period might be related to the number of stimuli administered during that period (100 trains-of-four, or 400 twitches, during 20 min). By administering a 2- or 5-s 50-Hz tetanus (100 or 250 twitches, respectively) to initiate the stabilization period, we assumed that we could speed stabilization. Our findings support this theory-either 2 or 5 s of tetanic stimulation preceding a 2-min stabilization period resulted in values for clinical recovery comparable to that with a 20-min stabilization period.

Three aspects of our study design warrant comment. First, studies in phase 1 were initially conducted because an investigation by Caldwell et al. [10] suggested a possible difference in the response of the dominant and nondominant extremity to vecuronium. The present studies indicate instead that either hand can be used for neuromuscular monitoring. Second, we administered a smaller dose of vecuronium (30 micro gram/kg) than did McCoy et al. [1] (80 micro gram/kg). Our dose was selected to achieve nearly complete twitch depression with minimal time to complete recovery, thereby minimizing potential effects of time on the stability of our neuromuscular monitoring. Third, because we measured twitch tension, our results may not apply if neuromuscular function is assessed by electromyography.

Our results confirm that onset and time to 10%, 25%, and 75% recovery of twitch tension vary as a function of the duration of nerve stimulation before drug administration and whether a tetanic stimulus is administered. In addition, our results suggest that investigators should report whether final recovery approximated initial twitch tension and whether clinical duration was referenced to predrug or recovery control. If investigators permit stabilization for an inadequate period, but must give additional doses of muscle relaxant or are otherwise unable to record twitch tension to full recovery, a 2-s or a 5-s tetanus during the stabilization period appears to obviate the need for a lengthy stabilization period.

The authors thank Dr. Dilworth Cannon for providing patients for the study.

REFERENCES

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Larijani GE, Bartkowski RR, Azad SS, Seltzer JL, Weinberger MJ, Beach CA, Goldberg ME: Clinical pharmacology of pipecuronium bromide. Anesth Analg 1989; 68:734-9.

Basta SJ, Savarese JJ, Ali HH, Embree PB, Schwartz AF, Rudd GD, Wastila WB: Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant. Anesthesiology 1988; 69:478-86.

Murray DJ, Mehta MP, Choi WW, Forbes RB, Sokoll MD, Gergis SD, Rudd GD, Abou-Donia MM: The neuromuscular blocking and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide narcotic anesthesia. Anesthesiology 1988; 69:472-7.

Viby-Mogensen J, Engbaek J, Eriksson L, Gramstad L, Jensen E, Jensen FS, Koscielniak-Nielsen Z, Skovgaard LT, Ostergaard D: Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40:59-74.

Engbaek J, Skovgaard LT, Friis B, Kann T, Viby-Mogensen J: Monitoring of the neuromuscular transmission by electromyography (I). Stability and temperature dependence of evoked EMG response compared to mechanical twitch recordings in the cat. Acta Anesthesiol Scand 1992; 36:495-504.

Eriksson LI, Lennmarken C, Jensen E, Viby-Mogensen J: Twitch tension and train-of-four ratio during prolonged neuromuscular monitoring at different peripheral temperatures. Acta Anaesthesiol Scand 1991; 35:242-52.

Heier T, Caldwell JE, Sessler DI, Kitts JB, Miller RD: The relationship between adductor pollicis twitch tension and core, skin, and muscle temperature during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology 1989; 71:381-4.

Caldwell JE, Szenohradszky J, Segredo V, Wright PM, McLoughlin C, Sharma ML, Gruenke LD, Fisher DM, Miller RD: The pharmacodynamics and pharmacokinetics of the metabolite 3-desacetylvecuronium (ORG 7268) and its parent compound, vecuronium, in human volunteers. J Pharmacol Exp Ther 1994; 270:1216-22.

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Table 1. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom Both Extremities Were Stimulated Identically (Phase 1)

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Table 2. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom Duration of Predrug Stimulation Differed between Extremities and No Tetanus Was Administered (Phase 2)

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Table 3. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom a 2-s Tetanus Was Administered to One Extremity (Phase 3)

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Table 4. Values for Magnitude and Time Course of Twitch Depression in Six Subjects in Whom a 5-s Tetanus Was Administered to One Extremity (Phase 4)

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