The Clinical Neuromuscular Pharmacology of 51W89 in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia 

The study was approved by the Institutional Review Board of The New York Hospital. All patients gave written informed consent for all monitoring, data collection, and anesthetic procedures. Ninety-nine patients, ASA physical status 1 or 2, undergoing low- to moderate-risk surgery were studied. Female patients of childbearing potential were excluded from the first part of this study. Thereafter, women eligible for enrollment were required to be nonpregnant and not lactating. Any patients with a history of neuromuscular, cardiovascular, pulmonary, renal, hepatic, or neurologic disorders were excluded. The mean patient ages and weights plus/minus SE were 39.3 plus/minus 0.9 yr and 77.4 plus/minus 1.3 kg, respectively.

On the day of the study, 20-G intravenous catheters were inserted, and midazolam (4–6 mg) was administered intravenously for sedation. Anesthesia was induced with thiopental (4–10 mg/kg) and fentanyl (29 mg/kg) intravenously in divided doses. Oxygen was delivered by face mask. The trachea was intubated without a relaxant, occasionally using lidocaine (4%) spray as a topical anesthetic. Ventilation was controlled throughout the study to maintain end-tidal carbon dioxide tension between 28 and 35 mmHg. Esophageal temperature was monitored and maintained between 35.5 degrees Celsius and 37.5 degrees Celsius by the use of warmed intravenous fluids and warming blankets. A 16-G intravenous catheter was inserted in the contralateral arm for blood sampling after the induction of anesthesia.

Anesthesia was maintained with nitrous oxide and oxygen (70:30), and additional doses of thiopental, fentanyl, and midazolam were given intravenously as needed to maintain a stable depth of anesthesia. The electrocardiogram was monitored continuously (Marquette model 700 or 710). Arterial pressure was measured by oscillometry (Dinamap), tonometry (N-CAT) or directly via a 20-G radial arterial cannula through a transducer. Heart rate was measured by oscillometry or, for the patients with arterial catheters, continuously by a Grass 7P44 tachograph triggered by the arterial pulse waveform. Hemodynamic data are presented in detail in a manuscript in press. [5].

The mechanomyogram of thumb adduction was quantitated with a Grass FTl0 force-displacement transducer. The supramaximal single twitch of the thumb was evoked at 0.15 Hz using square-wave pulses 0.2 ms in duration, generated by a Grass S88 stimulator and applied through a stimulus isolation unit to the ulnar nerve at the wrist via 23-G steel needle electrodes placed subcutaneously approximately 5 cm apart. Train- of-four stimulation (2 Hz for 2 s) was applied every 10 s during recovery from neuromuscular blockade.

All neuromuscular measurements and direct cardiovascular measurements were recorded simultaneously on a Grass Model 7 polygraph.

After a 3-min stable baseline period, 51W89 was injected rapidly (5–10 s) into a rapidly flowing intravenous fluid stream. Measurements of maximal twitch depression as well as arterial pressure and heart rate changes were obtained before any patient stimulation (surgery) was begun. In the first part of the study, a group of 39 patients received an initial 51W89 dose administered in divided doses totaling 0.15 mg/kg. One subgroup of three patients and four subgroups of nine patients received first dose portions of approximately ED¹⁰, ED²⁵, ED⁵⁰, ED⁷⁵, or ED⁹⁵. The first subgroup was administered a first dose portion of 0.04 mg/kg, which was estimated to be an ED²⁵dose based on preclinical studies in which 51W89 was about 30–50% more potent than atracurium. Log probit analysis of the accumulated dose-response data was used to determine the first dose portion for each subsequent subgroup. After maximal twitch suppression following the first dose portion was obtained, the second dose portion was administered, to bring the total initial dose to 0.15 mg/kg (Figure 2). In the second part of the study, separate patients received 2, 4, or 8 x ED⁹⁵boluses of 51W89 based on the results of the dose- response portion of the study. A control group received a 2 x ED⁹⁵bolus of atracurium (0.5 mg/kg) for comparison with 51W89. Recovery from neuromuscular block induced by the second dose portion of 51W89 was observed to at least 25% of control twitch height before an additional bolus of 0.025 mg/kg was given or a continuous infusion begun to maintain clinical relaxation.

The initial rate of infusion of 51W89 was 5 micro gram/kg/min for the first 39 patients and 3 micro gram/kg/min for subsequent patients receiving infusions. Neuromuscular block was maintained within the ranges of 90–99% by adjusting the infusion rate every 3 min until stable block was achieved. Recovery was allowed to proceed spontaneously in the odd-numbered patients at the end of surgery, or a single intravenous injection of 0.06 mg/kg neostigmine and 0.03 mg/kg atropine was administered to the even-numbered patients when the twitch response had recovered spontaneously to approximately 10% of the baseline value after the initial dose, at the termination of infusion, or after the last maintenance bolus dose. The rate of spontaneous recovery from neuromuscular blockade was measured and compared among the various dose groups and with the atracurium group. Spontaneous recovery from single bolus doses and infusions was compared with pharmacologically accelerated recovery. Recovery intervals from 5% to 95% and from 25% to 75% twitch heights after the initial bolus dose and after termination of infusions of 51W89 were compared to ascertain whether a cumulative pharmacodynamic effect was evident.

Data were analyzed using SAS software, version 6.07. Where confidence intervals were applied, an alpha level of 0.05 was used to define statistical significance. All data are presented as mean plus/minus SE.

Fade of train-of-four responses and facile antagonism by neostigmine (see below) were noted consistently at many levels of neuromuscular block. These observations are compatible with a nondepolarizing mechanism of block.

Dose-response data are summarized in Table 1and Table 2. The dose-response relationships were constructed from twitch suppression data obtained after the administration of the first portion of the initial doses of 51W89 in the first part of the study (Figure 2). Ordinary least-squares regression (linear regression) of the probit of maximum twitch suppression versus the common logarithm of the 51W89 dose was used to generate the dose-response line (Figure 3). All probit values were presented and analyzed on a scale of 2–8. If no block was observed, a probit value of 2 was assigned, and if complete block was observed, a probit value of 8 was assigned. The 51W89 ED⁹⁵and ED sub 50 neuromuscular blocking doses were estimated from the regression equation. The calculated ED⁹⁵for neuromuscular blockade was 0.048 mg/kg (95% confidence limits 0.03, 0.08). The calculated ED⁵⁰was 0.029 mg/kg (95% confidence limits 0.02, 0.05).

Increasing dosage of 51W89 resulted in shorter mean times to onset of maximum neuromuscular block. Onset at 0.4 mg/kg (1.9 plus/minus 0.1 min) was 3.3 min faster than at 0.10 mg/kg (5.2 plus/minus 0.3 min).

After 0.1 mg/kg (a 2 x ED⁹⁵dose), the mean duration from injection to recovery to 95% of control force of twitch was 64.4 plus/minus 3.9 min. After 0.2 and 0.4 mg/kg (4 and 8 x ED⁹⁵, respectively), recovery to 95% of control occurred in 87.0 plus/minus 4.3 and 121.0 plus/minus 5.9 min, respectively.

The clinical duration, i.e., time from injection to return to twitch to 25% of control, varied from 45.0 plus/minus 2.4 min after 0.1 mg/kg to 91.3 plus/minus 3.3 min after 0.4 mg/kg (2 and 8 x ED⁹⁵, respectively).

Mean recovery intervals from 5% to 95% and from 25% to 75% twitch height ranged from 29.6 to 32.3 min and from 12.6 to 14.3 min, respectively, after bolus doses of 0.1–0.4 mg/kg. They did not differ statistically. When plotted graphically, they appear as parallel recovery patterns (Figure 4). The mean recovery intervals for all subjects at all single bolus doses combined were 31.1 (n = 23) and 13.5 min (n = 24) for 5–95% and 25–75%, respectively.

The T4/T1 ratio reached greater or equal to 70% within 2.3- 5.3 min after the first twitch of the train-of-four had returned to 95% of control after bolus doses and within 3.5 min after infusions of 51W89.

The average infusion rate necessary to maintain approximately 95% twitch suppression was 1.4 micro gram/kg/min (n = 27) for 51W89 (Figure 5) and 5.6 micro gram/kg/min (n = 9) for atracurium.

Spontaneous recovery from continuous infusion of 51W89 occurred at rates similar to those observed after single bolus doses. (Table 2) Thirty-eight patients received infusions ranging in duration from 11 to 249 min (mean 109.2 min). Eighteen infusions lasted 2 h or longer. Mean 5–95% and 25–75% recovery indexes during spontaneous recovery from these infusions were 33.2 plus/minus 1.8 (n = 8) and 15.0 plus/minus 0.6 min (n = 19), respectively. These data were compared with recovery indexes from all single bolus doses and were not statistically different. The data show that recovery is independent of dose or duration of infusion at the dosages studied and over the range of infusions reported in this study (Figure 6).

Twenty-five patients received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at between 6% and 21%(mean 12.6 plus/minus 0.7%) twitch height during recovery from the initial dose or after discontinuation of the infusion. Antagonism to 95% of control twitch force developed within 6.8 plus/minus 0.3 min (3.9–10.8 min). The neostigmine-accelerated 25–75% recovery index was 2.8 plus/minus 0.2 min.

This study has shown 51W89 to be a potent nondepolarizing neuromuscular blocking agent. When the ED⁹⁵of atracurium is expressed in terms of its cation, rather than the besylate salt, 51W89 is approximately 3 times more potent as a neuromuscular blocking agent than atracurium. At doses up to the ED⁹⁵(0.02–0.05 mg/kg), the onset of 51W89 (7 min) is slower than atracurium (3–4 min)[6] and faster than doxacurium (10 min). [7] This observation is consistent with their relative potencies because the more potent nondepolarizing neuromuscular blockers seem to have a slower onset. [8].

Six isomers of atracurium, including 51W89, were tested by Wastila and Maehr in cats and were found to have varying potencies. The onset time to maximum block varied inversely with potency, although all isomers have the same chemical composition and molecular weight and differ only in terms of stereochemistry. [3] The 51W89 isomer is more potent than atracurium in humans, thus a somewhat slower onset would be anticipated. Onset of action for larger doses of 51W89 is dose-related. For example, by increasing the dose from 0.1 to 0.2 to 0.4 mg/kg (from 2 to 4 to 8 x ED⁹⁵), onset to maximum block was shortened from 5.2 to 2.7 and 1.9 min, respectively. The time to and ease of intubation were not evaluated in the current study. It has been shown, however, that intubation can be accomplished in 89% of patients 2 min after a 2 x ED sub 95 dose of 51W89 (0.1 mg/kg). [9] Equipotent doses of vecuronium produce slightly faster onset times of 3.8 and 2.8 min, [10] and a 2 x ED⁹⁵dose of rocuronium produces maximal block in 1.5 min when onset is measured by repetitive train-of-four stimulation. [11].

The duration of action of 51 W89 is similar to that reported for atracurium at equipotent doses [6] and the clinical duration of a 2 x ED⁹⁵dose (45.0 min) was the same as atracurium in this study and similar to reported values for vecuronium (36.3 min) and rocuronium (40 min). [11] This duration is more than twice as long as mivacurium [12](19.7 min) and about half as long as pancuronium [13](115.8) and doxacurium [7](82.9 min). The clinical duration of effect increased only 150% and 200% with a 4 x ED⁹⁵dose (68.3 min) and an 8 x ED⁹⁵dose (91.3 min), respectively. The total duration increased about 23 min with a doubling of dose (Table 2), suggesting that 51W89 will have an elimination half-life of about 23 min, similar to atracurium. Additionally, the consistent pattern of recovery independent of size of bolus dose or length of infusion suggests that 51W89 displays noncumulative pharmacodynamics with recovery always occurring during the drug's elimination phase. [14].

51W89′s spontaneous 25–75% recovery index of approximately 14 min is comparable to the other intermediate-duration nondepolarizing neuromuscular blockers vecuronium, 14.3 min [13]; rocuronium, 16.7 min [11]; and atracurium, 11.8 min. [6].

Antagonism of residual block was accomplished easily once some evidence of spontaneous recovery was detected by administration of neostigmine and atropine. The 25–75% recovery index decreased to 2.8 min. The speed of reversal was comparable to reversal of mivacurium- and atracurium-induced block at a similar depth, with T1 of the train-of- four response returning to 95% within 7 min after injection of neostigmine.

The intermediate duration of action and lack of cumulative neuromuscular blocking effects of 51W89, like atracurium, probably are due to its decomposition and metabolism by Hofmann elimination, which is independent of hepatic or renal function.

In summary, 51W89, one of the ten stereoisomers of atracurium, is a potent intermediate-duration nondepolarizing neuromuscular blocking agent. Its pharmacodynamics are similar to atracurium: Duration and recovery profile are essentially the same and are independent of dose. Neuromuscular block is easily maintained at a stable level by infusion at a constant rate and does not diminish over time. Rate of recovery is independent of the duration of administration by infusion. Recovery can be accelerated with an anticholinesterase agent if needed. These attributes and 51W89′s probable lack of dependence on renal or hepatic metabolism suggest that the new drug should be a positive addition to the anesthesiologist's armamentarium of neuromuscular blocking drugs, especially if its cardiovascular effects are absent in humans as in the preclinical studies. Further studies of its pharmacokinetics, hemodynamic effects, and pharmacodynamics in special populations are warranted.