Intramuscular Rapacuronium in Infants and Children: A Comparative Multicenter Study to Confirm the Efficacy and Safety of the Age-related Tracheal Intubating Doses of Intramuscular Rapacuronium (ORG 9487) in Two Groups of Pediatric Subjects

The Institutional Review Boards at each center approved this study (Massachusetts General Hospital, Boston, MA; Children’s National Medical Center, Washington, DC; Children’s Hospital Medical Center, Chicago, IL; Duke University Medical Center, Durham, NC). Informed written consent was obtained from the parents or legal guardians of the 96 patients enrolled. All subjects were classified as American Society of Anesthesiologists physical status I or II. Of these 96 subjects, 46 were infants (aged 1–12 months) and 50 were children (aged 1–3 yr;table 1). Of the 46 infants, 15 were randomized for attempted tracheal intubation at 1.5 min, 15 were randomized to the 3-min tracheal intubation time, and 16 were randomized to the 4-min tracheal intubation time. Of the 50 children, 17 were randomized for attempted tracheal intubation at 1.5 min, 17 were randomized at 3 min, and 16 were randomized at 4-min tracheal intubation time. All subjects were undergoing surgery in which a nitrous oxide–oxygen, halothane anesthetic was appropriate. Patients were excluded if they weighed more than 16.5 kg; had abnormalities of their airway; had significant renal, hepatic, metabolic, or neuromuscular disorders; had bleeding disorders; or were receiving drugs known to interfere with neuromuscular function. Nine subjects were excluded from analysis because of protocol violation. Of the nine protocol violations, seven were subjects not receiving the investigational drug, one was excluded because of inappropriate randomization, and one was excluded because the wrong dose of rapacuronium was given (table 2).

No premedicants were used. Anesthesia was induced with halothane and nitrous oxide–oxygen via  a face mask. A pulse oximeter, electrocardiogram, and noninvasive blood pressure cuff were applied. An intravenous catheter was placed after loss of eyelid reflex. Anesthesia was maintained with halothane and oxygen at an end-tidal concentration of 1% in patients younger than 2.5 yr and 0.80% end-tidal concentration in patients older than 2.5 yr. After anesthetic induction and intravenous placement, nitrous oxide was discontinued. Rapacuronium was given 5 min after the discontinuation of nitrous oxide. Rapacuronium was given in all cases within 15 min of starting the anesthetic. End-tidal carbon dioxide was monitored in all subjects, and normocapnia was maintained using assisted ventilation if required. After induction of anesthesia, the ulnar nerve was stimulated at the wrist with surface electrodes using supramaximal square-wave train-of-four stimulus administered at 2 Hz every 20 s (Dual Stim Peripheral Nerve Stimulator, Life-Tech, Houston, TX). Neuromuscular monitoring of the force of adduction of the adductor pollicis was recorded using a mechanomyograph. The transducer used was a Grass F20 (Grass Instruments, Quincy, MA) or Myotrace (Life-Tech, Inc.), and a strip chart recording was obtained. A baseline tension of 50–100 g was applied to the thumb. Before calibration of the strip chart recording, a 50-Hz tetanic stimulus was delivered for 2 s. After baseline stabilization, which required a minimum of 5 min, infants received 2.8 mg/kg rapacuronium intramuscularly and children received 4.8 mg/kg of rapacuronium intramuscularly into the deltoid as a single bolus injection. The arm on the opposite side to the neuromuscular monitoring equipment was used to administer the rapacuronium via  a 22- or 23-gauge needle. The time at which tracheal intubation was attempted was determined from a randomization table. After the administration of rapacuronium, an experienced laryngoscopist (one of the principal investigators at each institution, who was blinded to the time of injection) entered the room and was told when to begin the laryngoscopy. The choice of laryngoscope blade was at the discretion of the laryngoscopist. Depending on the randomization schedule, laryngoscopy was attempted at 1.5 min, 3 min, or 4 min after administration of rapacuronium. The experienced laryngoscopist then scored the intubation using the criteria shown in table 3.

After laryngoscopy and tracheal intubation, anesthesia was maintained with 60% nitrous oxide in oxygen and 0.8–1 minimum alveolar concentrations of halothane. Fentanyl was used for analgesia as clinically indicated. If clinically appropriate, recovery of neuromuscular function was allowed to proceed spontaneously to a twitch recovery of 90% as compared with final twitch response, if possible. However, if spontaneous neuromuscular recovery did not occur by the end of the procedure, residual neuromuscular block was reversed with 0.02 mg/kg atropine and 0.07 mg/kg neostigmine. The site of the intramuscular injection was assessed for redness, swelling, and bruising 5 min after injection and at the conclusion of surgery. Histamine-related clinical findings such as erythema, hives, or bronchospasm were recorded.

Pharmacodynamic parameters were expressed as the mean (± SD), median, and range. Peak effect, onset time, time to 95% block, time from rapacuronium injection to 25%, 50%, and 90% recovery of the twitch height (T1), and the return of T4:T1 to 70% between treatment groups, age groups, and centers were compared using a three-way analysis of variance. The Cochran-Mantel-Haenszel procedure was used to identify the difference in intubating conditions between treatment groups and age groups. Results were considered significant at P  less than 0.05.

Patients in each age group and each subgroup in the age group at institutions were comparable with respect to age, height, weight, gender, race, and American Society of Anesthesiologists physical status (table 1).

Intubating conditions were unacceptable in the majority of patients at 1.5 or 3 min after administration of rapacuronium in both groups. Tracheal intubating conditions were acceptable at 4 min in 64% of infants and 71% of children (table 4). Eleven subjects failed intubation at the first attempt and were all given a rating of poor.

In both infants and children, a mean twitch suppression more than or equal to 95% was achieved. Time to more than or equal to 95% twitch depression (onset) was 6.0 ± 3.7 min in infants and 5.5 ± 3.8 min in children. T1 (% of control) at 2 min was 67 ± 28% in infants and 67 ± 27% in children. The time for recovery of T1 to 25% of twitch height was 34.8 ± 11.7 min in infants (n = 33) and 43.8 ± 21.6 min in children (n = 29). The time for 90% spontaneous recovery of T1 to baseline twitch was 73.2 ± 21.3 min in infants (n = 17) and 106.0 ± 31.1 min in children (n = 6). The recovery index (T1, 25–75%) was 25 ± 12.4 min in infants (n = 22) and 56.2 ± 47.7 min in children (n = 11). Spontaneous recovery to a train-of-four ratio of 80% was obtained in 17 infants and 4 children and was 82.4 ± 18.5 in infants and 143 ± 16.1 in children. In assessing onset and recovery data, onset data were calculated using the initial twitch height of the initial train-of-four stimulus. Spontaneous recovery data were calculated using the final twitch height whenever possible. Reversal was administered if the T4/T1 ratio was less than 0.70 at the conclusion of the procedure (table 5).

Adverse events occurred in 20 infants and 22 children. Two in the children’s group were classified as serious. The serious adverse events were from one site: prolonged neuromuscular block in one patient and bronchospasm in another. In the subject who developed bronchospasm, it was rated as moderate in intensity, occurring as a response to tracheal intubation. Resolution of bronchospasm occurred after an increase in inspired halothane. The patient with prolonged neuromuscular block appeared weak postoperatively, despite full recovery of train-of-four response. In neither patient were there any long-term sequelae. All other adverse events noted were swelling or erythema at the injection site. The swelling and erythema had resolved by the end of surgery in all patients. There were no deaths during the study, and no subjects were discontinued from the study because of adverse events.

In the present study, we did not obtain adequate intubating conditions in the majority of patients at 1.5 and 3 min after 2.8 mg/kg rapacuronium in infants and 4.8 mg/kg in children at 1 minimum alveolar concentration end-tidal halothane. When laryngoscopy was attempted 4 min after the administration of rapacuronium, the tracheal intubating conditions were acceptable in 64% and 71% of infants and children, respectively. Consequently, we do not recommend the use of intramuscular rapacuronium for tracheal intubation in infants and children while undergoing light halothane anesthesia.

This multicenter study could not confirm results of the previous study by Reynolds et al. , 11in which 2.8 mg/kg intramuscular rapacuronium given to infants and 4.8 mg/kg intramuscular rapacuronium given to children provided adequate tracheal intubating conditions in 2.5–3.0 min after drug administration. We used similar concentrations of halothane and administered rapacuronium as a single dose intramuscularly into the deltoid and used the same scale for assessing the ease of laryngoscopy and tracheal intubation conditions (table 3). In the present study, only senior anesthesiologists performed the laryngoscopies and intubations at each center, and they were blinded as to the time elapsed from the rapacuronium administration. In the pilot study, it was shown that at 1.5 min after administration of rapacuronium, poor intubation conditions were present, but at 2.5 min good tracheal intubating conditions were obtained. 11We could not confirm this finding.

In the pilot study, maximum twitch depression occurred at 5.7 ± 2.9 min in infants and 5.5 ± 2.7 min in children. 11This is similar to the time taken for maximum twitch depression to develop in the subjects in the present study. However, despite the similarity of the times to twitch depression, we did not find tracheal intubating conditions to be as good in the multicenter trial as those in the pilot study. Recovery of T1 to 10% of initial twitch in both infants and children was comparable in both the pilot study and the multicenter study (table 6). This would imply that the uptake, distribution, and metabolism in the subjects from both studies were similar. 11,12 

This study was conducted in a similar manner to the previous multicenter study assessing intramuscular rocuronium. 13That study, based on a pilot study, assessed onset, intubating conditions, and recovery after intramuscular rocuronium 1 mg/kg in infants and 1.8 mg/kg in children. 14In that study, the conditions for tracheal intubation were poor in the majority of subjects at 2.5 min after intramuscular rocuronium. After extending the time before attempting tracheal intubation, conditions improved, with 56% of the infants having acceptable conditions at 3.5 min after rocuronium. 13When tracheal intubation was attempted in the children at 4.5 min after rocuronium, 58% of the subjects had acceptable conditions. 13This was despite the fact that the pilot study had found excellent intubating conditions using the same techniques. 14Onset, or the time to maximum block, after intramuscular rocuronium was 7.4 ± 3.4 min and 8.9 ± 6.3 min in infants and children, respectively. 13The onset after rapacuronium in our study was slightly faster at 6.0 ± 3.7 min and 5.5 ± 3.8 min in infants and children, respectively. The time for recovery after intramuscular rapacuronium tended to be faster than recovery after intramuscular rocuronium. The time for T1 to recover to 90% of initial twitch height after intramuscular rocuronium was 112 ± 36 min and 120 ± 29 min in infants and children, respectively. 13In contrast, after intramuscular rapacuronium, recovery of T1 to 90% of initial twitch height took 73.2 ± 21.3 min and 106 ± 39.1 min in infants and children, respectively. These data confirm the observations from the intravenous studies that rapacuronium has a shorter duration of action than the intermediate acting relaxant rocuronium. 6,11,12 

Succinylcholine is the recommended intramuscular relaxant because of rapid onset and a relatively brief duration of action. However, to the best of our knowledge, there has not been a study that has properly studied intubating conditions when succinylcholine has been given intramuscularly. Clinical experience has shown that the drug is effective for tracheal intubation when given intramuscularly, but the experience of most pediatric anesthesiologists is very limited in this respect. Neuromuscular studies have shown that twitch depression of more than 90% occurs when succinylcholine is given intramuscularly at a dose of 3–4 mg/kg. The inspired halothane concentration in those studies was 2% in one study and not specified in the other. 8,9 

Based on present data, it is difficult to make a specific recommendation for the ideal muscle relaxant that can be used in the absence of intravenous sites. Clinical experience and neuromuscular data have shown that intramuscular succinylcholine has the fastest onset (4 min) and the fastest recovery. Of the relaxants tested, mivacurium was found to be ineffective when given intramuscularly. 15Rocuronium and rapacuronium have onset times that are relatively slow i.e. , 6–7 min, with durations of action of more than 1 h. Perhaps if the clinician were willing to wait more than 5 min before attempting tracheal intubation or increase the depth of anesthesia, the conditions would become satisfactory. In the scenario of laryngospasm, lack of intravenous access, and decreasing arterial oxygen saturation, intramuscular succinylcholine would be the decision of choice. However, if the situation is not urgent, muscle relaxation can be supplemented by intramuscular rapacuronium or rocuronium. Because laryngeal and respiratory muscles are affected before the peripheral muscles, tracheal intubation would be possible before the twitch response was ablated at the thumb. 16,17This onset differential may allow easier face mask ventilation before tracheal intubation is possible.

Intramuscular relaxants may be needed less frequently with increasing use of long-term central venous access and the availability of anesthetic agents such as sevoflurane, which may have a safer profile (better cardiovascular stability) than halothane and produce less coughing or laryngospasm than older anesthetics. 18,19 

We have no specific explanation for the differences between this study and the pilot study. However, we would further reiterate that it is important that multicenter, well-controlled, blinded trials are used to verify and corroborate single-center studies. 20 

Our study does not support the hypothesis that rapacuronium in the doses used provides adequate intubating conditions within 3 min of drug administration when using 1 minimum alveolar concentration halothane anesthesia, thereby greatly diminishing the synergistic effect of the volatile agent. This was by design, as the investigators were keen to insure that the intramuscular neuromuscular blocking drug, rapacuronium, and not the inhalational anesthetic, was providing the intubating conditions.

This multicenter study showed that 27% of patients achieved clinically acceptable tracheal intubating conditions at 1.5 or 3 min after intramuscular administration of 2.8 mg/kg and 4.8 mg/kg rapacuronium during light halothane anesthesia. The tracheal intubations at 4 min were acceptable in 69% of subjects. The duration of action of 4.8 mg/kg rapacuronium in children was longer than 2.8 mg/kg rapacuronium in infants. We cannot recommend intramuscular rapacuronium at the doses studied as an acceptable muscle relaxant to facilitate tracheal intubation at 1.5 or 3 min after administration, because of its slow onset. Further study is needed to evaluate the role intramuscular rapacuronium in the relief of laryngospasm.

The authors thank Jane Cyran, Ph.D. (Senior Director, Clinical Projects), Tiffany Woo, M.S. (Clinical Development Team Leader), Kao-tai Tsai, Ph.D. (Assistant Director, Biostatistics), and Huang Hsu, Ph.D. (Biostatistician), all of Organon, Inc., West Orange, New Jersey. Dr. Cyran was involved in protocol development and Ms. Woo was responsible for project coordination. Drs. Tsai and Hsu were responsible for statistical analysis.