- Email: [email protected]
Pharmacodynamic effects of three doses of ORG 9426 used for endotracheal intubation in humans
Pharmacodynamic Effects of Three Doses of ORG 9$26 Used for Endutracheal Intubation in Humans Michel Y. Dubois, MD,* Genevi&ve Lapeyre, MD,? Dawn Lea, RN, BSN,$ Dung Q. Tran, MD& Bideshwar K. Kataria, MD5 Department
Washington,
of Anesthesia, DC.
Georgetown
University
Medical Center,
Objective: To determine the pharmacodynamic characteristics of three incremental doses of ORG 9426 used f or endotracheal intubation in patients. Design: Double-blind, randomized administration of one of three doses of intravenous ORG 9426. Setting: Inpatients requiring surgery at Georgetown University Medical Center. Patients: Thirty-six patients, ages 18 to 65, ASA physical status I, II, and III, scheduled for general surgery. Interventions: After Georgetown University Institutional Review Board approval and patient consent, patients were premeditated with midazolam or droperidol. Anesthesia was induced with thiopental sodium andfentanyl. Anesthesia was maintained with 60%> nitrous oxide in oxygen. The ulnar nerve was stimulated supramaximally with a 2 Hz train-of-four (TOF) every 20 seconds. Thumb contractions were measured with a force transducer. When TOF and anesthesia were stable, 2,2.5, or 3 times the ED,, of ORG 9426 (570 pglkg, 710 kglkg, or 850 pglkg) was administered randomly. Tracheal intubation was attempted at maximal depression of the first TOF response (T,). Measurements and Main Results: The following parameters were measured: time interval from the injection of ORG 9426 to 90% depression of T, (T, 90% block), maximal T, depression (onset time), intubating conditions, clinical duration (time for return of T, to 25% of control), heart rate (HR), blood pressure (BP), and any adverse clinical experience. ORG 9426 provided adequate intubating conditions in all patients but two, independent of the dose used. Its onset time was rapid, but increasing the dose did not shorten the onset. T, 90% block was achieved rapidly (75 +- 25 seconds to 78 t 18 seconds, means 2 SD). The clinical duration of ORG 9426 was relatively short and lengthened with increasing doses (from 36 +- 18 minutes at 570 kglkg to 42 2 IO minutes at 850 kglkg. Spontaneous twitch recovery from 10% to 25% was similar in all dosage groups (5 +- I minutes to 6 +- 4 minutes). No clinically significant changes in HR and BP and no adverse clinical experiences were noted in any group Conclusion: These findings warrant further clinical evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans. Study
*Professor University
of
Anesthesia,
Georgetown
tAssistant Professor, Hopital St. Vincent de Paul, Paris, France fClinical Research Coordinator, Department of Anesthesia, Georgetown University SAssistant Professor of Anesthesia, Georgetown University Address reprint requests to Dr. Dubois at the Department of Anesthesia, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007-2197, USA. Supported by an educational grant from the French Foreign Office (Bourse Lavoisier) and, in part, by a grant from Organon, Inc., West Orange, NJ. Received for publication January 17, 1992; revised manuscript accepted for publication June 30, 1992. 0 1992 Butterworth-Heinemann J. Clin. Anesth. 4~472-475, 1992.
472
J. Clin. Anesth.,
Keywords: Intubation, endotracheal; neuromuscular nondepolarizing; ORG 9426; steroids.
blocking
drugs,
Introduction ORG 9426, a nondepolarizing neuromuscular ternary derivative of an analog of vecuronium
vol. 4, November/December
1992
blocking bromide.
drug, is a monoquaIn animals, this new
Phrmucodynamics of ORG 9424: Dubois et al.
steroid muscle relaxant has been found to have a fast onset of action, a potency 15% that of vecuronium, and a shorter duration than vecuronium.r.2 In preliminary dose-response studies in humans, however, its duration was found to be similar to that of vecuronium, with no apparent cardiovascular effects. The ED,, determined in humans with balanced anesthesia was found to be 285 kg/kg3. The goal of this study was to determine the pharmacodynamic characteristics of three doses of ORG 9426 (2, 2.5, and 3 times EDg5) and to evaluate these three doses to facilitate adult endotracheal intubation.
Materials and Methods After Georgetown University Institutional Review Board approval and patient informed consent, 36 patients, ASA physical status I, II, and III, who were scheduled for general surgery expected to last more than 1 hour were enrolled in the study. Patients under 18 or over 65 years old; women of childbearing potential; patients with known significant renal, hepatic, metabolic, or neuromuscular disorders; patients with obesity; and patients chronically receiving antihistamines or drugs that may modify the action of neuromuscular blocking drugs were excluded. Each patient was randomized to receive one of three intubation dosages: ORG 9426 570, 710, or 850 kg/kg intravenously (IV), corresponding, respectively, to 2,2.5, and 3 times ED,,. After IV premeditation with either midazolam 2 to 5 mg/kg or droperidol 2.5 to 5 mg/70 kg, anesthesia was induced with thiopental sodium 3 to 7 mg/kg and fentanyl 1 to 10 Fg/kg. Anesthesia maintenance during the protocol period was provided by 60% nitrous oxide in oxygen and increments of fentanyl and thiopental sodium as necessary. Once the patient was unconscious, as determined by loss of eyelid reflex, thumb adduction response to nerve stimulation was measured using a force transducer (Myotrace Model APM, Professional Instruments, Houston, TX). A resting tension of 200 to 300 g was applied to the thumb. The ulnar nerve was stimulated at the wrist through surface electrodes with train-of-four (TOF) supramaximal square-wave impulses of 0.2 msec duration at 2 Hz every 10 seconds. The muscle twitch response was recorded continuously on a polygraph. Before the administration of ORG 9426, a stable baseline recording was obtained where all four TOF responses were nearly equal and reproducible for 1 minute. The assigned randomized dose of ORG 9426 was then injected rapidly, and endotracheal intubation was attempted at maximal depression of the first twitch (T,) of the TOF response. During the study period, end-tidal partial pressure of carbon dioxide was maintained between 35 and 40 mmHg and esophageal temperature was maintained between 35.5” and 37” C. When T, returned to 25% of control, if additional muscle relaxation was required, vecuronium bromide was administered, and neuromuscular blockade monitoring for the study protocol was discontinued. The following pharmacodynamic parameters were measured: time interval (seconds) from the completion
of the ORG 9426 injection to (1) 90% depression of T, (T,90) and (2) the maximal T, depression (onset time); the maximal T, depression as a percentage of control twitch height (peak effect); intubating conditions (assessment by an independent observer was standardized and scored as excellent if the jaws were relaxed, the vocal cords were apart and immobile, and there was no diaphragmatic movement; good if the above were met except for diaphragmatic movement; poor if the vocal cords were moving and there was coughing or bucking; and inadequate if, in addition to the above criteria, the jaw was not relaxed); time (minutes) from the end of the ORG 9426 injection to spontaneous recovery of T, to 25% of the control value (clinical duration); and time interval (minutes) between T, 10% and 25% of control during spontaneous recovery (T, 10-25). Electrocardiography and heart rate (HR) were monitored continuously. HR and noninvasive blood pressure (BP) were recorded as follows: (1) prior to and after induction; (2) prior to administration of the ORG 9426 intubating dose (defined as baseline); (3) at peak effect before intubation; (4) at 2minute intervals during the study period. Intraoperative adverse effects such as histamine-related clinical findings (e.g., erythema or bronchospasm) were recorded. As a routine screening procedure, prior to and after surgery a thorough physical examination and comprehensive blood and urine analyses were performed. Results expressed are means 2 SD. All results of hypothesis testing were considered statistically significant if the two-tailed p-value did not exceed 0.05. Statistical computations and hypothesis testing were performed using SAS software, version 5.18 (SAS Institute, Box 8000, Cary, NC). Demographic and pharmacodynamic data were analyzed using one-way analysis of variance (ANOVA) to compare the uniformity of the three groups. If the overall comparison was significant at the p c 0.05 level, the Fisher’s least significant difference technique was used to perform pairwise comparisons. Cardiovascular data analysis was performed within each dosage group using paired difference t-tests to evaluate the statistical significance of a percent change from baseline. Comparisons among the three dosage groups for percent change from baseline at peak effect also were performed using one-way ANOVA.
Results There were no significant demographic differences among the groups with respect to age, height, weight, and sex (Table 1). The onset time was rapid and did not change significantly with increasing doses. Maximum peak effect (0% of control) was achieved in most patients in all dosage groups. Three patients in the lowest dosage group kept a minimum twitch response (c 3%). The pharmacodynamic findings concerning the neuromuscular block are summarized in Table 2. Endotracheal intubation, carried out after maximum twitch depression, was possible in all patients. Two patients in the 850 Fg/ kg dosage group presented poor intubation conditions. J. Clin. Anesth.,
vol. 4, November/December
1992
473
Original Contribution In all other patients, intubation conditions were rated as either excellent or good (Table 3). In five patients, diaphragmatic movements were noted, although the condition of relaxation of the laryngeal muscles was optimal. The mean clinical duration of increasing doses of ORG 9426 increased from 36 -+ 18 minutes for the low-dose group (2 x EDg5) to 42 2 10 minutes for the high-dose group (3 x ED,,) without reaching statistical significance. Spontaneous recovery of the first twitch of the TOF from 10% to 25% (T, 10-25) did not differ significantly in the three groups. The recovery times were short and predictable regardless of the dose given. They were shorter than those obtained with vecuronium (about 10 minutes) in a similar experimental design. No significant cardiovascular effects directly related to ORG 9426 could be found with the three doses used in this study. In two patients, bradycardia (less than 50 beats per minute) was observed but required no treatment. Otherwise, no clinically significant changes in HR and
Table
1.
Demographic Data Dosage Group
Age (yr) Weight (kg) Height (cm) ASA (physical I II III Sex Male Female
570 (I.g/kg
710 pg/kg
850 cl.gflrg
48 r 11 66 + 11 169 * 9
43 + 12 72 2 18 171 * 11
45 2 14 71 +- 10 173 + 11
10 2 0
6 5 1
4 7 1
;
6 6
7 5
status)
Note:
Data are means
Table
2.
+- SD.
Pharmacodynamic
Parameters
Dosage Group 570 pglkg (n = 12)
710 pglkg
850 pglkg
(n = 12)
(n = 12)
T,90 (set) Onset (set) Completed intubation
78 t 18 115 * 34
75 2 25 114 2 39
77 -c 30 114 z+z51
(set) Duration T, 1 O-25
140 t 24t 36 * 18 6?4
147 1 40 39 ? 8 5+1
148 + 61 42 ? 10 5+3
Parameter*
(min) (min)
*Parameters are defined as follows: T,90 = time from the completion of ORG 9426 injection to 90% depression of T,; onset = time from the completion of ORG 9426 injection to maximal T, depression; completed intubation = time from the completion of ORG 9426 injection to completed intubation; duration = time from the completion of ORG 9426 injection to spontaneous recovery of T, to 25% of control; T1lO-15 = time between T, 10% and 25% of control during spontaneous recovery. tBased require
on 11 patients. One patient endotracheal intubation.
with a tracheostomy
474
J. Clin. Anesth., vol. 4, November/December
did not
1992
Table 3.
Intubation
Conditions Dosage Group
Parameter
570 pg/kg*
710 pg/kg
850 pglkg
Total
Excellent Good Poor Inadequate
8 3 0 0
10 2 0 0
10 0 2 0
28 5 2 0
*One patient
Table 4.
had a tracheotomy
Percent
Change
preoperatively.
at Peak Effect Dosage Group
Heart ratei Mean SD Lowest Highest Systolic/diastolic blood pressure? Mean SD
Lowest Highest *Three effect.
patients
tFrom
baseline.
570 pg/kg (n = 9)*
710 @kg (n = 12)
-3
-9
-4 11 -23 16
-21-2 10113 -151-18 12124
-31-4 1019 ~ 19/- 14 14/l 1
6 8
were excluded
because
of intubation
850 pglkg (n = 12)
-4 1.5 -42 11
oi - 1 11120 - 151-22 19137 prior
to peak
BP were found in relation to the drug. At peak effect of the intubating dose and prior to endotracheal intubation, percent changes of baseline values were minimal and similar within the dosage range examined (Table 4). No patient demonstrated evidence of histamine release, as manifested by flushing, tachycardia, bronchospasm, or hypotension. Postoperative physical examination and laboratory evaluations did not demonstrate drug-related changes when compared with preoperative values. Discussion The purpose of this study was to evaluate the pharmacodynamic response of patients who received one of three doses of ORG 9426 and to assess intubation conditions obtained with these three doses. The ED,, of ORG 9426 used in this study3 was slightly lower than the ED,, reported elsewhere.4,6,7 The onset time was found to be approximately 60% of the onset time obtained with similar experimental modalities and with an equipotent dose of vecuronium (100 pg/kg, 2 X EDgJ.5 The time period from the end of the injection and the first visible decrease of the twitch response, referred to as lag time, was even more rapid. This onset, however, had an atypical appearance: T,90 was reached in about 1 minute, and the completion of the onset of the block (peak effect) oc-
Pharmacodynamics
A ORG
9426
Injection
of ORG 9426:
Dubois et al.
A
A Block
Peak Effect
Starts
Figure 1. In patients where the onset time was longer than average, the neuromuscular block developed rapidly up to about 803 and then more slowly.
cur-red approximately 1 minute later. The intensity of the neuromuscular block increased rapidly at first, up to about SO%, then considerably more slowly. This type of onset was observed primarily in patients in which the onset time was longer than average (Figure 1). At the same time, it was observed that the T,/T, ratio showed a measurable decrease immediately at the onset of the block. Possible effects on presynaptic cholinoceptors have been both suggested8 and disproved9 to explain the rapid onset and biphasic aspect of the block. This rapid onset of neuromuscular blockade provided good to excellent intubation conditions; poor conditions were exhibited in 2 of 35 patients. In five patients, diaphragmatic movements were noted in spite of optimum relaxation of the laryngeal muscles. These movements were probably related to the relative resistance of the diaphragm to this nondepolarizing muscle relaxant and to a light level of anesthesia. Onset time, peak effect, and intubation conditions were not affected by increasing the dosage of ORG 9426. The frequency distribution among the three dosage groups for those parameters was similar. In conclusion, the major features of ORG 9426 were a characteristic rapid initial phase of onset and adequate intubation conditions with all doses used. There was no obvious advantage to using more than 2 x ED,, (i.e., 570 kg/kg) to facilitate endotracheal intubation. T,90 was reached within 1 minute, but endotracheal intubation was not attempted before obtaining the peak effect. With vecuronium, it was reported that endotracheal intubation could be successful at 80% to 90% T, depression.*” It is possible that the same technique may be applied to ORG 9426, which would significantly shorten the intubation time. The clinical duration and spontaneous recovery of ORG 9426 are marginally shorter than those of vecuronium. The onset and spontaneous recovery characteristics of the drug were independent of the amount given within the dose range of this protocol. No cardiovascular or other clinically adverse effects could be detected in any of the patients. These findings justify further evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans.
Acknowledgments We are most grateful to Ming Liang for his technical help; Bose, PhD, biostatistician at Organon, Inc., for help in the analysis of the results from our study; and to Kenneth PhD, clinical project director at Organon, Inc., for his help and collaboration throughout this project.
to Anjana checking Spencer, sustained
References 1. Muir AW, Houston J, Green KL, Marshall RJ, Bowman WC, Marshall IG: Effects of a new neuromuscular blocking agent (ORG-9426) in anesthetized cats and pigs and in isolated nervemuscle preparations. BrJ Anaesth 1989;63:400-10. 2. Cason B, Baker DC, Hickey RF, Miller RD, Agoston, S: Cardiovascular and neuromuscular effects of three steroid neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991). Anesth Analg 1990;70:382-8. 3. Nagashima H, Nguyen HD, Kinsey A, et al.: The human dose response of ORG 9426 [Abstract]. Anesthesiology 1989;7 1 :A773. 4. Wierda JMKH, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S: The pharmacodynamics and pharmacokinetics of ORG 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. CanJ Anuesth 1991;38:430-5. 5. Kaufman JA, Dubois MY, Chen JC, Lea DE: Pharmacodynamic effects of vecuronium: A dose response study. J Clin An&h 1989; 1:434-g. 6. Foldes FF, Nagashima H, Nguyen HD, Schiller WS, Mason MM, Ohta Y: The neuromuscular effects of ORG 9426 in patients receiving balanced anesthesia. Anesthesiology 1991;75:191-6. 7. Booij LHDJ, Knape HTA: The neuromuscular effect of ORG 9426, a new, intermediate-acting steroidal nondepolarizing muscle relaxant in man. Amesthesza 1991;46:341-3. 8. Wierda JMKH, de Wit APM, Kuizenga K, Agoston S: Clinical observations on the neuromuscular blocking action of ORG 9426, a new steroidal non-depolarizing agent. Br J Anuesth 1990;64:521-3. 9. Watanabe K, Chen K, Ohta Y, Nagashima H, Foldes FF: The pre- and postsynaptic effects of ORG 9426 during onset of recovery from neuromuscular blockade [Abstract]. Anesthesiology 1991;75:A798. 10. Baird WLM, Savage Anesth 1985;3:347-60.
1. Clin.
Anesth.,
DS: Vecuronium-the
vol. 4, November/December
first
years.
1992
Clin
475
Washington,
of Anesthesia, DC.
Georgetown
University
Medical Center,
Objective: To determine the pharmacodynamic characteristics of three incremental doses of ORG 9426 used f or endotracheal intubation in patients. Design: Double-blind, randomized administration of one of three doses of intravenous ORG 9426. Setting: Inpatients requiring surgery at Georgetown University Medical Center. Patients: Thirty-six patients, ages 18 to 65, ASA physical status I, II, and III, scheduled for general surgery. Interventions: After Georgetown University Institutional Review Board approval and patient consent, patients were premeditated with midazolam or droperidol. Anesthesia was induced with thiopental sodium andfentanyl. Anesthesia was maintained with 60%> nitrous oxide in oxygen. The ulnar nerve was stimulated supramaximally with a 2 Hz train-of-four (TOF) every 20 seconds. Thumb contractions were measured with a force transducer. When TOF and anesthesia were stable, 2,2.5, or 3 times the ED,, of ORG 9426 (570 pglkg, 710 kglkg, or 850 pglkg) was administered randomly. Tracheal intubation was attempted at maximal depression of the first TOF response (T,). Measurements and Main Results: The following parameters were measured: time interval from the injection of ORG 9426 to 90% depression of T, (T, 90% block), maximal T, depression (onset time), intubating conditions, clinical duration (time for return of T, to 25% of control), heart rate (HR), blood pressure (BP), and any adverse clinical experience. ORG 9426 provided adequate intubating conditions in all patients but two, independent of the dose used. Its onset time was rapid, but increasing the dose did not shorten the onset. T, 90% block was achieved rapidly (75 +- 25 seconds to 78 t 18 seconds, means 2 SD). The clinical duration of ORG 9426 was relatively short and lengthened with increasing doses (from 36 +- 18 minutes at 570 kglkg to 42 2 IO minutes at 850 kglkg. Spontaneous twitch recovery from 10% to 25% was similar in all dosage groups (5 +- I minutes to 6 +- 4 minutes). No clinically significant changes in HR and BP and no adverse clinical experiences were noted in any group Conclusion: These findings warrant further clinical evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans. Study
*Professor University
of
Anesthesia,
Georgetown
tAssistant Professor, Hopital St. Vincent de Paul, Paris, France fClinical Research Coordinator, Department of Anesthesia, Georgetown University SAssistant Professor of Anesthesia, Georgetown University Address reprint requests to Dr. Dubois at the Department of Anesthesia, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007-2197, USA. Supported by an educational grant from the French Foreign Office (Bourse Lavoisier) and, in part, by a grant from Organon, Inc., West Orange, NJ. Received for publication January 17, 1992; revised manuscript accepted for publication June 30, 1992. 0 1992 Butterworth-Heinemann J. Clin. Anesth. 4~472-475, 1992.
472
J. Clin. Anesth.,
Keywords: Intubation, endotracheal; neuromuscular nondepolarizing; ORG 9426; steroids.
blocking
drugs,
Introduction ORG 9426, a nondepolarizing neuromuscular ternary derivative of an analog of vecuronium
vol. 4, November/December
1992
blocking bromide.
drug, is a monoquaIn animals, this new
Phrmucodynamics of ORG 9424: Dubois et al.
steroid muscle relaxant has been found to have a fast onset of action, a potency 15% that of vecuronium, and a shorter duration than vecuronium.r.2 In preliminary dose-response studies in humans, however, its duration was found to be similar to that of vecuronium, with no apparent cardiovascular effects. The ED,, determined in humans with balanced anesthesia was found to be 285 kg/kg3. The goal of this study was to determine the pharmacodynamic characteristics of three doses of ORG 9426 (2, 2.5, and 3 times EDg5) and to evaluate these three doses to facilitate adult endotracheal intubation.
Materials and Methods After Georgetown University Institutional Review Board approval and patient informed consent, 36 patients, ASA physical status I, II, and III, who were scheduled for general surgery expected to last more than 1 hour were enrolled in the study. Patients under 18 or over 65 years old; women of childbearing potential; patients with known significant renal, hepatic, metabolic, or neuromuscular disorders; patients with obesity; and patients chronically receiving antihistamines or drugs that may modify the action of neuromuscular blocking drugs were excluded. Each patient was randomized to receive one of three intubation dosages: ORG 9426 570, 710, or 850 kg/kg intravenously (IV), corresponding, respectively, to 2,2.5, and 3 times ED,,. After IV premeditation with either midazolam 2 to 5 mg/kg or droperidol 2.5 to 5 mg/70 kg, anesthesia was induced with thiopental sodium 3 to 7 mg/kg and fentanyl 1 to 10 Fg/kg. Anesthesia maintenance during the protocol period was provided by 60% nitrous oxide in oxygen and increments of fentanyl and thiopental sodium as necessary. Once the patient was unconscious, as determined by loss of eyelid reflex, thumb adduction response to nerve stimulation was measured using a force transducer (Myotrace Model APM, Professional Instruments, Houston, TX). A resting tension of 200 to 300 g was applied to the thumb. The ulnar nerve was stimulated at the wrist through surface electrodes with train-of-four (TOF) supramaximal square-wave impulses of 0.2 msec duration at 2 Hz every 10 seconds. The muscle twitch response was recorded continuously on a polygraph. Before the administration of ORG 9426, a stable baseline recording was obtained where all four TOF responses were nearly equal and reproducible for 1 minute. The assigned randomized dose of ORG 9426 was then injected rapidly, and endotracheal intubation was attempted at maximal depression of the first twitch (T,) of the TOF response. During the study period, end-tidal partial pressure of carbon dioxide was maintained between 35 and 40 mmHg and esophageal temperature was maintained between 35.5” and 37” C. When T, returned to 25% of control, if additional muscle relaxation was required, vecuronium bromide was administered, and neuromuscular blockade monitoring for the study protocol was discontinued. The following pharmacodynamic parameters were measured: time interval (seconds) from the completion
of the ORG 9426 injection to (1) 90% depression of T, (T,90) and (2) the maximal T, depression (onset time); the maximal T, depression as a percentage of control twitch height (peak effect); intubating conditions (assessment by an independent observer was standardized and scored as excellent if the jaws were relaxed, the vocal cords were apart and immobile, and there was no diaphragmatic movement; good if the above were met except for diaphragmatic movement; poor if the vocal cords were moving and there was coughing or bucking; and inadequate if, in addition to the above criteria, the jaw was not relaxed); time (minutes) from the end of the ORG 9426 injection to spontaneous recovery of T, to 25% of the control value (clinical duration); and time interval (minutes) between T, 10% and 25% of control during spontaneous recovery (T, 10-25). Electrocardiography and heart rate (HR) were monitored continuously. HR and noninvasive blood pressure (BP) were recorded as follows: (1) prior to and after induction; (2) prior to administration of the ORG 9426 intubating dose (defined as baseline); (3) at peak effect before intubation; (4) at 2minute intervals during the study period. Intraoperative adverse effects such as histamine-related clinical findings (e.g., erythema or bronchospasm) were recorded. As a routine screening procedure, prior to and after surgery a thorough physical examination and comprehensive blood and urine analyses were performed. Results expressed are means 2 SD. All results of hypothesis testing were considered statistically significant if the two-tailed p-value did not exceed 0.05. Statistical computations and hypothesis testing were performed using SAS software, version 5.18 (SAS Institute, Box 8000, Cary, NC). Demographic and pharmacodynamic data were analyzed using one-way analysis of variance (ANOVA) to compare the uniformity of the three groups. If the overall comparison was significant at the p c 0.05 level, the Fisher’s least significant difference technique was used to perform pairwise comparisons. Cardiovascular data analysis was performed within each dosage group using paired difference t-tests to evaluate the statistical significance of a percent change from baseline. Comparisons among the three dosage groups for percent change from baseline at peak effect also were performed using one-way ANOVA.
Results There were no significant demographic differences among the groups with respect to age, height, weight, and sex (Table 1). The onset time was rapid and did not change significantly with increasing doses. Maximum peak effect (0% of control) was achieved in most patients in all dosage groups. Three patients in the lowest dosage group kept a minimum twitch response (c 3%). The pharmacodynamic findings concerning the neuromuscular block are summarized in Table 2. Endotracheal intubation, carried out after maximum twitch depression, was possible in all patients. Two patients in the 850 Fg/ kg dosage group presented poor intubation conditions. J. Clin. Anesth.,
vol. 4, November/December
1992
473
Original Contribution In all other patients, intubation conditions were rated as either excellent or good (Table 3). In five patients, diaphragmatic movements were noted, although the condition of relaxation of the laryngeal muscles was optimal. The mean clinical duration of increasing doses of ORG 9426 increased from 36 -+ 18 minutes for the low-dose group (2 x EDg5) to 42 2 10 minutes for the high-dose group (3 x ED,,) without reaching statistical significance. Spontaneous recovery of the first twitch of the TOF from 10% to 25% (T, 10-25) did not differ significantly in the three groups. The recovery times were short and predictable regardless of the dose given. They were shorter than those obtained with vecuronium (about 10 minutes) in a similar experimental design. No significant cardiovascular effects directly related to ORG 9426 could be found with the three doses used in this study. In two patients, bradycardia (less than 50 beats per minute) was observed but required no treatment. Otherwise, no clinically significant changes in HR and
Table
1.
Demographic Data Dosage Group
Age (yr) Weight (kg) Height (cm) ASA (physical I II III Sex Male Female
570 (I.g/kg
710 pg/kg
850 cl.gflrg
48 r 11 66 + 11 169 * 9
43 + 12 72 2 18 171 * 11
45 2 14 71 +- 10 173 + 11
10 2 0
6 5 1
4 7 1
;
6 6
7 5
status)
Note:
Data are means
Table
2.
+- SD.
Pharmacodynamic
Parameters
Dosage Group 570 pglkg (n = 12)
710 pglkg
850 pglkg
(n = 12)
(n = 12)
T,90 (set) Onset (set) Completed intubation
78 t 18 115 * 34
75 2 25 114 2 39
77 -c 30 114 z+z51
(set) Duration T, 1 O-25
140 t 24t 36 * 18 6?4
147 1 40 39 ? 8 5+1
148 + 61 42 ? 10 5+3
Parameter*
(min) (min)
*Parameters are defined as follows: T,90 = time from the completion of ORG 9426 injection to 90% depression of T,; onset = time from the completion of ORG 9426 injection to maximal T, depression; completed intubation = time from the completion of ORG 9426 injection to completed intubation; duration = time from the completion of ORG 9426 injection to spontaneous recovery of T, to 25% of control; T1lO-15 = time between T, 10% and 25% of control during spontaneous recovery. tBased require
on 11 patients. One patient endotracheal intubation.
with a tracheostomy
474
J. Clin. Anesth., vol. 4, November/December
did not
1992
Table 3.
Intubation
Conditions Dosage Group
Parameter
570 pg/kg*
710 pg/kg
850 pglkg
Total
Excellent Good Poor Inadequate
8 3 0 0
10 2 0 0
10 0 2 0
28 5 2 0
*One patient
Table 4.
had a tracheotomy
Percent
Change
preoperatively.
at Peak Effect Dosage Group
Heart ratei Mean SD Lowest Highest Systolic/diastolic blood pressure? Mean SD
Lowest Highest *Three effect.
patients
tFrom
baseline.
570 pg/kg (n = 9)*
710 @kg (n = 12)
-3
-9
-4 11 -23 16
-21-2 10113 -151-18 12124
-31-4 1019 ~ 19/- 14 14/l 1
6 8
were excluded
because
of intubation
850 pglkg (n = 12)
-4 1.5 -42 11
oi - 1 11120 - 151-22 19137 prior
to peak
BP were found in relation to the drug. At peak effect of the intubating dose and prior to endotracheal intubation, percent changes of baseline values were minimal and similar within the dosage range examined (Table 4). No patient demonstrated evidence of histamine release, as manifested by flushing, tachycardia, bronchospasm, or hypotension. Postoperative physical examination and laboratory evaluations did not demonstrate drug-related changes when compared with preoperative values. Discussion The purpose of this study was to evaluate the pharmacodynamic response of patients who received one of three doses of ORG 9426 and to assess intubation conditions obtained with these three doses. The ED,, of ORG 9426 used in this study3 was slightly lower than the ED,, reported elsewhere.4,6,7 The onset time was found to be approximately 60% of the onset time obtained with similar experimental modalities and with an equipotent dose of vecuronium (100 pg/kg, 2 X EDgJ.5 The time period from the end of the injection and the first visible decrease of the twitch response, referred to as lag time, was even more rapid. This onset, however, had an atypical appearance: T,90 was reached in about 1 minute, and the completion of the onset of the block (peak effect) oc-
Pharmacodynamics
A ORG
9426
Injection
of ORG 9426:
Dubois et al.
A
A Block
Peak Effect
Starts
Figure 1. In patients where the onset time was longer than average, the neuromuscular block developed rapidly up to about 803 and then more slowly.
cur-red approximately 1 minute later. The intensity of the neuromuscular block increased rapidly at first, up to about SO%, then considerably more slowly. This type of onset was observed primarily in patients in which the onset time was longer than average (Figure 1). At the same time, it was observed that the T,/T, ratio showed a measurable decrease immediately at the onset of the block. Possible effects on presynaptic cholinoceptors have been both suggested8 and disproved9 to explain the rapid onset and biphasic aspect of the block. This rapid onset of neuromuscular blockade provided good to excellent intubation conditions; poor conditions were exhibited in 2 of 35 patients. In five patients, diaphragmatic movements were noted in spite of optimum relaxation of the laryngeal muscles. These movements were probably related to the relative resistance of the diaphragm to this nondepolarizing muscle relaxant and to a light level of anesthesia. Onset time, peak effect, and intubation conditions were not affected by increasing the dosage of ORG 9426. The frequency distribution among the three dosage groups for those parameters was similar. In conclusion, the major features of ORG 9426 were a characteristic rapid initial phase of onset and adequate intubation conditions with all doses used. There was no obvious advantage to using more than 2 x ED,, (i.e., 570 kg/kg) to facilitate endotracheal intubation. T,90 was reached within 1 minute, but endotracheal intubation was not attempted before obtaining the peak effect. With vecuronium, it was reported that endotracheal intubation could be successful at 80% to 90% T, depression.*” It is possible that the same technique may be applied to ORG 9426, which would significantly shorten the intubation time. The clinical duration and spontaneous recovery of ORG 9426 are marginally shorter than those of vecuronium. The onset and spontaneous recovery characteristics of the drug were independent of the amount given within the dose range of this protocol. No cardiovascular or other clinically adverse effects could be detected in any of the patients. These findings justify further evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans.
Acknowledgments We are most grateful to Ming Liang for his technical help; Bose, PhD, biostatistician at Organon, Inc., for help in the analysis of the results from our study; and to Kenneth PhD, clinical project director at Organon, Inc., for his help and collaboration throughout this project.
to Anjana checking Spencer, sustained
References 1. Muir AW, Houston J, Green KL, Marshall RJ, Bowman WC, Marshall IG: Effects of a new neuromuscular blocking agent (ORG-9426) in anesthetized cats and pigs and in isolated nervemuscle preparations. BrJ Anaesth 1989;63:400-10. 2. Cason B, Baker DC, Hickey RF, Miller RD, Agoston, S: Cardiovascular and neuromuscular effects of three steroid neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991). Anesth Analg 1990;70:382-8. 3. Nagashima H, Nguyen HD, Kinsey A, et al.: The human dose response of ORG 9426 [Abstract]. Anesthesiology 1989;7 1 :A773. 4. Wierda JMKH, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S: The pharmacodynamics and pharmacokinetics of ORG 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. CanJ Anuesth 1991;38:430-5. 5. Kaufman JA, Dubois MY, Chen JC, Lea DE: Pharmacodynamic effects of vecuronium: A dose response study. J Clin An&h 1989; 1:434-g. 6. Foldes FF, Nagashima H, Nguyen HD, Schiller WS, Mason MM, Ohta Y: The neuromuscular effects of ORG 9426 in patients receiving balanced anesthesia. Anesthesiology 1991;75:191-6. 7. Booij LHDJ, Knape HTA: The neuromuscular effect of ORG 9426, a new, intermediate-acting steroidal nondepolarizing muscle relaxant in man. Amesthesza 1991;46:341-3. 8. Wierda JMKH, de Wit APM, Kuizenga K, Agoston S: Clinical observations on the neuromuscular blocking action of ORG 9426, a new steroidal non-depolarizing agent. Br J Anuesth 1990;64:521-3. 9. Watanabe K, Chen K, Ohta Y, Nagashima H, Foldes FF: The pre- and postsynaptic effects of ORG 9426 during onset of recovery from neuromuscular blockade [Abstract]. Anesthesiology 1991;75:A798. 10. Baird WLM, Savage Anesth 1985;3:347-60.
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