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Rocuronium priming of atracurium-induced neuromuscular blockade: The use of short priming intervals
ELSEVIER
Rocuronium Priming of Atracurium-Induced Neuromuscular Blockade: The Use of Short Priming Intervals Mohamed Abdulatif, MD,* Abduhnohsin Al-Ghamdi, MD,? Mohga El-Sanabary, MD$
Department of Anesthesia, Faculty of Medicine, Cairo University, Cairo, Egypt; Department of Anesthesia, King Faisal University, Al-Khobar, Saudi Arabia.
*Associate Professor t.Assistant Professor ~Lecturer Address correspondence to Dr. Abdulatif at the Department of Anesthesiology, King Fahad Hospital of the University, M-Khobar 31952, P.O. Box 40081, Saudi Arabia. Received for publication July 6, 1995; revised manuscript accepted for publication November 7. 1995.
Study Objective: To evaluate the effects of p riming doses of rocuronium on the duration of priming interval and on the outcome ofpriming sequence using rocuronium-atracurium combination. Design: Three phase, randomized, controlled study. Setting: Inpatient anesthesia in a university hospital. Patients: 144 ASA physical status I and IIpatients, 19 to 57 years of age, weighing 50 to 90 kg, and undergoing low-risk elective surgery. Interventions: Phase I, two equal grou;bs (n = 12) of adult patients anesthetized with propofol, fentanyl, and nitrous oxide (N,O), received a priming dose of rocuronium 0.1 mg/kg or vecuronium 0.015 mg/kg. Phase II included six equal groups (n = 12): Groups 1, 2, and 3 received a priming dose of rocuronium 0.1 mg/kg and atracurium 0.42 mg/kg for intubation. The priming intervals were, respectively, 1, 1.5, or 2 minutes in Groups 1, 2, and 3. Groups 4, 5, and 6 received, respectively, a bolus dose ofrocuronium 0.6 mg/kg atracurium 0.5 mg/kg, or succinylcholine 1 mg/kg. Intubation was performed at maximum block. Phase III included four equal groups {n = 12). A ptiming dose of rocuronium 0.1 mg/kg (Group 1) or a placebo (Groups 2, 3, and 4) was given to awake patients. Anesthesia was induced during the one-minute priming interval. Intubating doses of atracum’um 0.42 mg/kg, rocuronium 0.6 mg/kg, atracurium 0.5 mg/kg, or succinylcholine 1 mg/kg were given to Groups 1, 2, 3, and 4, respectively. Intubation was attempted 1 minute after intubating doses were administered. Measurements and Main Results: Add&or pollicis response to train-of-four stimulation was recorded mechanically in Phases I and II only. The priming interval after rocuronium 0.1 mg/kg was in the range of 1 to 2 minutes. Priming doses of rocuronium resulted in signijcant acceleration in the onset time of intubating doses of atracurium, iwespective of the duration of the priming interual. The onset times [mean (SD)] following rocuronium-atracurium sequence in Groups 1, 2, and 3 were, respectively, 67 (17), 73 (14), and 66 (18) seconds and were comparable with the onset of bolus dosesof rocuronium and succinylcholine. In Phase II, good to excellent intubating conditions were obtained in 41% to 58% of patients included in Groups 1 through 5. Excellent to good intubating conditions were obtained in all patients (100%) who received succinylcholine. In Phase
Journal of Clinical Anesthesia 8:376-381, 1996 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0952~8180/96/$15.00 PI1 SO952-8180(96)00078-5
Priming with rocuronium: Abdulatif et al.
III, good to excellent intubating conditions were obtained in 91% of patients who received rocuronium-atracurium sequence. Symptoms of muscle weakness were not reported. Conclusions: Priming doses of rocuronium 0.1 mg/kg reduce the priming interval to 1 minute, allow early induction of anesthesia, eliminate patient discomfort, and accebzrate the onset time of atracurium with i&abating conditions comparable with sucn’nylcholine and rocuronium.
Keywords: Intubation: relaxants: rocuronium, priming principle.
endotrachial; atracurium,
neuromuscular pharmacodynamics:
cations with known or suspected effects on neuromuscular transmission. All patients were premeditated with oral diazepam 10 mg, given approximately 90 minutes before surgery. In the operating room, lactated Ringer’s solution with 5% dextrose was commenced intravenously (IV) before induction of anesthesia. The present study was conducted in three phases. In the first two phases, neuromuscular blockade was monitored with the use of a force displacement transducer and neuromuscular blockers were administered after induction of anesthesia. The third phase examined the clinical relevance of the data obtained in Phases I and II.
Introduction
Phase I Mechanomyogw@hic Study
Rapid sequence induction of anesthesia should be carefully performed, with special attention to the possibility of hypoxia and aspiration of gastric contents. The time-delay between inducing anesthesia and securing the airway should be considered a danger period, which should be shortened as much as possible.’ With the use of the priming technique to accelerate the onset of atracurium or vecuronium, a priming interval of 3 to 5 minutes is usually required.2Z3 During this relatively long priming interval, awake patients may suffer from distressing symptoms of muscle weakness, eg, blurred vision, dysphagia, and respiratory embarrassment.4Z5 The risk of pulmonary aspiration also may increase.6 Rocuronium bromide is a new, intermediate-acting neuromuscular blocking drug with a rapid onset of action.’ Priming doses of rocuronium recently have been used to accelerate the onset time of intubating doses of rocuronium and mivacurium.8 Naguib’ suggested that the rapid onset of rocuronium may make it the drug of choice with the priming technique. However, the possible advantages of the rapid onset of rocuronium on the priming sequence were not evaluated. The aim of the present study was to examine the hypothesis that the rapid onset of rocuronium may reduce the priming interval. The effects of priming doses of rocuronium on the onset time and intubating conditions following intubating doses of atracurium were also evaluated.
The objective of this phase of the study was to examine the time course of action of priming doses of rocuronium to choose the spectrum of potentially effective priming intervals to be subsequently evaluated in Phase II. Rocuronium was compared with the slower acting analogue vecuronium. Twenty-four patients were included in this phase of the study. Anesthesia was induced in all patients with fentany12 pg/kg and propofo12.5 to 3 mg/kg. An appropriately sized laryngeal mask was used to maintain the airway. Anesthesia was then maintained with nitrous oxide (N,O) 70% in oxygen (0,) and additional doses of propofol as required. Ventilation was controlled to maintain normocapnia [end-tidal CO, partial pressure (P,,CO,) 35 to 40 mmHg] . Nasopharyngeal temperature was monitored and maintained at a level of 35.5”C to 37°C. Arterial blood pressure, ECG, O,% saturation, concentrations of N,O and P&O, were continuously monitored by a Cardiocap II monitor (Datex Instrumentarium Corporation, Helsinki, Finland). After induction of anesthesia, the ulnar nerve was stimulated at the wrist using supramaximal square pulses of 0.2 ms duration, delivered in a train-of-four (TOF) sequence at 2 Hz. The TOF pattern of nerve stimulation was automatically repeated every 10 seconds, using a Myotest peripheral nerve stimulator (Biometer International, Odense, Denmark). The resulting contractions of the adductor pollicis muscle were recorded using a force displacement transducer and a neuromuscular function analyzer (Myograph 2000, Biometer International, Odense, Denmark). Preload tension on the thumb was maintained at 300 g throughout the investigation. After stabilization of twitch height recording, patients were randomly allocated via closed envelope to one of two equal groups (n = 12) according to the type of neuromuscular blocking drug. Patients in Group 1 received one single IV bolus of rocuronium 0.1 mg/kg while patients in Group 2 received vecuronium 0.015 mg/kg. These priming doses of rocuronium and vecuronium are equipotent and are equivalent to approximately one-third the ED,,.‘*l’ The effect of these doses on the first twitch height (T,) and on the TOF ratio (fractional height of the fourth to the first response in the TOF sequence T4/T1) was continuously recorded until the development of maximum block.
Materials
and Methods
One hundred and forty-four ASA physical status I and II male and female adult patients aged 19 to 57 years (mean 32.6 yrs) and weighing 50 to 90 kg [mean 69 (SD 9.4) kg], were enrolled in this study. All patients were undergoing low-risk, elective surgery. The study was approved by the King Fahad University Hospital Ethics Committee, and all patients gave written informed consent. The following patients were excluded: those with asthma, those at high risk of aspiration and those in whom difficult intubation was anticipated. We also excluded from the study any patient suffering from cardiac, vascular, respiratory, hepatic, renal, or neuromuscular disorder, and those receiving medi-
J. Clin.
Anesth.,
vol. 8, August
1996
377
Original Contributiwu
Maximum block was defined as the point at which no further decrease was observed in the evoked response of the adductor pollicis muscle to three consecutive stimuli. This phase of the study was terminated at this stage and subsequent anesthetic management was continued as appropriate for surgery. The following parameters were determined for each patient: (1) twitch stabilization time: the time interval in minutes between induction of anesthesia and the development of stable twitch height recordings; (2) time interval between the end of injection of the priming dose of neuromuscular blocking drug and the first appreciable fade in the evoked response (lag time); (3) time required for the development of maximum block; and (4) T, and TOF ratio at maximum block.
Phase II Mechanomyographic Study Seventy-two patients anesthetized and monitored as in Phase I were included. During the twitch stabilization period, anesthesia was maintained with 70% N,O in 0, delivered via a face mask. After stabilization of twitch height recordings, patients were randomly allocated to one of six equal groups (n = 12)) according to the type of neuromuscular blocking drug, its method of administration, and the duration of the priming interval. Groups 1, 2, and 3 received a priming dose of rocuronium 0.1 mg/kg followed by an intubating dose of atracurium 0.42 mg/kg. The priming intervals were, respectively, 1, 1.5, or 2 minutes in Groups 1, 2, and 3 (Table I). These priming intervals were selected in view of the results obtained in Phase I. Groups 4, 5, and 6 received single bolus doses of rocuronium 0.6 mg/kg, atracurium 0.5 mg/kg, or succinylcholine 1 mg/ kg, respectively. Saline placebo injections preceded the administration of intubating doses of neuromuscular blocker in Groups 4, 5, and 6. Endotracheal intubation was performed in all patients by the same experienced anesthetist at maximum block. Intubating conditions (Table 2) were evaluated by an observer who was unaware of the patient’s group. No additional doses of propofol or fentanyl were given before endotracheal intubation. After intubation, anesthesia was maintained with 70% N,O in 02, incremental doses of fentanyl, and a continuous infusion of propofol. The following parameters were determined for all pa-
Table 1.
Priming interval (h)
Primiig relaxant (WW
1
Rocuronium 0.1 Rocuronium 0.1 Rocuronium 0.1
1.5 2
-
-
1
*Significantly different from other groups. 378
J.
Grading of Intubating Conditions
Score 0
1 2 3
Intubating
Adapted from Fahey et al.”
tients: (1) twitch stabilization time, as in Phase I, (2) T, height and TOF ratio at the time of administration of the intubating dose of neuromuscular blocking drugs, (3) onset of block: the time interval between the end of injection of the intubating dose and the development of maximum block, and (4) time required for 10% spontaneous recovery of T,.
Clinical Study Forty-eight patients were included in this part of the study. A rapid-sequence induction of anesthesia was used. Patients were randomly allocated to one of four equal groups (n = 12) according to the type and the method of administration of neuromuscular blocking drugs (Table 3). A priming dose of rocuronium 0.1 mg/kg or a placebo was administered to awake patients after preoxygenation with 100% 0, for 3 minutes. Patients were informed about the possible consequences of the priming dose such as diplopia, heaviness in the eye lids, dysphagia, or difficulty in breathing. They were requested to report the occurrence of any of these symptoms before loss of consciousness. Based on the results of Phase II, a one-minute priming interval was used in the clinical part of this study. This brief priming interval was used for the induction of anesthesia using fentanyl 2 pg/kg and propofol 2.5 to 3 mg/ kg. Cricoid pressure was applied by an assistant just after the loss of verbal contact with patients. Group 1 patients received intubating doses of atracurium 0.42 mg/kg.
Clin. Anesth., vol. 8, August 1996
De.gree of block before intubating doses of relaxants Tl
(%)
81 (9) 71 (19) 69 -
(22) -
conditions
Cords abducted, good visualization, no patient movement Cords abducted, good visualization, diaphragmatic movement with intubation Cords slightly adducted, fair visualization, coughing with intubation Cords adducted, difficult visualization, gross body movements, and coughing with intubation
Priming Parameters and Neuromuscular Data in Different Mechanomyographic
Group (n = 12)
2 3 4 5 6
Table 2.
TOF (%) 75 (9) 54 (17) 48 (21)" - - - -
Groups [mean (SD) I
Onset time kc)
Intubating relaxant (mdkg)
Atracurium Atracurium Auacurium Rocuronium Atracurium Succinylcholine
0.42 0.42 0.42 0.60 0.50
1.00
67 73 66 56 114 57
(17) (14) (18) (12) (29)$ (17)
Tl
(10%) (mW
45 45 48 30
(S)* (6)* (4)"
(7)
28 (8) 8.4 (2)*
Primingwith rocuronium: Abdulatif& al. Table 3.
Priming Parameters and Intubating Conditions in Different Mechanomyographic Mechunomyographic
Groups
Priming Group (n = 12)
Priming relaxant @&it)
1
Rocuronium 0.1 Rocuronium 0.1 Rocuronium 0.1 -
2 3 4 5 6
interval (mm
1 1.5 2 -
and Clinical Groups
Intubation Intobating relaxant (mdkg)
Atracurium Atracurium Atacurium Rocuronium Atracurium Succinylcholine
0.42 0.42 0.42 0.60 0.50 1.00
Score
% of good to excellent intobating conditions
0
1
2
3
1
6
6 4 4 6 4 6
5 7 4 4 5 0
0 0 3 I 2 0
6 5 2 9
5 5 2 3
1
0
91”
2 3 0
0 5 0
83” 33 100”
1 1
1 1
58 41 41 58 41 100*
Clinical Groups
1 2 3 4 *Significantly
Rocuronium 0.1 different
1 -
Atracurium Rocuronium Atracurium Succinylcholine
0.42 0.60 0.50 1.00
from other groups.
Groups 2, 3, and 4 received, respectively, single bolus intubating doses of rocuronium 0.6 mg/kg, atracurium 0.5 mg/kg, or succinylcholine 1 mg/kg. Intubation was attempted in all patients one minute after the administration of the intubating dose of neuromuscular blocking drug, Intubating conditions were evaluated as in Phase II. Oxygen saturation was continuously monitored during induction and was recorded at the time of intubation. After the data were recorded, the anesthetist in charge of the case was informed about the relaxant(s) given so that he/she could plan the remainder of the anesthetic. Assessment of neuromuscular transmission, based on visual observation of the response of the hand muscles to ulner nerve stimulation, was started only after intubation. Statistical analyses were performed on the neuromuscular data by unpaired Student’s t test, one-way analysis of variance (ANOVA), and Student-Newman-Keuls test for multiple comparisons, as appropriate. Intubating conditions were compared with Kruskall-Wallis and chi-square tests. A p-value less than 0.05 was considered statistically significant. Results were expressed as means (SD).
Results Phase I Mechanomyographic Study The time required for stabilization of twitch height recording was 6.4 (1.5) minutes. Priming doses of rocuronium and vecuronium produced similar degrees of block in the first twitch and in the TOF response, However, the time course of action of rocuronium was significantly shorter than that of vecuronium. Appreciable degrees of neuromuscular blockade were evident after a lag time of 45 (12) and 115 (48) seconds following priming doses of rocuronium and vecuronium, respectively (p < 0.01). The times required for the development of maximum block following rocuronium and vecuronium were, respectively, I48
(21) and 312 (45) seconds (p < 0.01). Two minutes after the administration of the priming dose of rocuronium, T, and TOF ratio were ‘74.8% (16%) and 56% (14%)) respectively. These values were not statistically different from the T, and TOF ratio recorded at maximum block (Figure 1).
Phase II Mechanomyographic Study Twitch stabilization time was similar to Phase I. Priming doses of rocuronium resulted in significant fade in T, and in TOF response, before the administration of intubating doses of neuromuscular blocking drugs. The magnitude of first twitch depression (T,) was comparable in all priming groups (Groups 1,2, and 3). However, the fade in the TOF response was more pronounced in Group 3 patients who were allowed a two-minute priming interval (Table I). Complete suppression of TOF response (100% block) was obtained after intubating doses of neuromuscular blocking drugs in all patients. Priming doses of rocuronium resulted in significant acceleration in the onset time of subsequent intubating doses of atracurium irrespective of the duration of the priming interval. Bolus doses of atracurium were associated with the longest onset time
(Table 1). Good to excellent intubating conditions (scores of 0 and 1) were obtained in 41% to 58% of patients included in Groups 1 through 5. There were no statistically significant differences in the intubating scores between these groups. In contrast, excellent to good intubating conditions were obtained in all patients (100%) who received succinylcholine (Table 3). The duration of neuromuscular blockade in Groups 1, 2, and 3 who received rocuronium-atracurium sequence were, respectively, 45 (8), 45 (6), and 48 (4) minutes, and were significantly longer than other groups. Succinylcholine was associated with the shortest duration of action
(Table 1). J. Clin. Anesth., vol. 8, August 1996
379
Original Contributions 100 T
-
Tl Vecuronium
- 0 - Tl Rocuronium
90 --
-
T4 Vecuronium
- . - T4 Rocuronium
E .o 8O -H “0 !g 70 -5 E .P 2 60-F
*
‘.
\
. . -. * *
50 --
44-l
: : : : f : : : ( : : : : I 0 0.5 1.5 2.5 3.5 6.5 4.5 5.5 Time (minutes)
Figure 1. Time course of action and pattern of first twitch (T,) and train-of-four (TJ fade following priming doses of rocuronium and vecuronium. Error bars were omitted for the sake of clarity. *Significantly different compared with vecuronium group.
Clinical Study Priming doses of rocuronium, followed one minute later by intubating doses of atracurium (Groups I), were associated with good to excellent intubating conditions in 91% of patients (Table 3). These were comparable to intubating conditions obtained with bolus doses of rocuronium and succinylcholine. Intubating conditions in clinical group 1 were significantly better than in the mechanomyographic group who received the same doses of neuromuscular blocking drugs separated by a similar priming interval (mechanomyographic Groups 1). None of the patients reported any symptom of subjective muscle weakness before losing consciousness. Oxygenation was well maintained in all patients with a mean 0, saturation of 98.2 (1.3)% at the time of intubation.
In the present study, analysis of the time course of action of priming doses of rocuronium demonstrated that appreciable fade in the adductor pollicis response was detectable at 0.75 minutes, with a maximum block at 2.5 minutes. The degree of neuromuscular blockade recorded 380
J. Clin. Anesth., vol. 8, August 1996
after 2 minutes was not different from that obtained at maximum block. This finding implies that with the use of priming doses of rocuronium, effective neuromuscular block is present after a priming interval of 1 minute, and waiting more than 2 minutes is unnecessary. In the second phase of this study, priming doses of rocuronium significantly reduced the onset time of intubating doses of atracurium. The magnitude of this reduction reached about 50% and was not affected by the duration of the priming interval. However, the two-minute priming interval was associated with significantly lower TOF ratio at the time of administration of intubating doses (Table I). Therefore, the optimum priming interval after priming doses of rocuronium appears to be in the range of 1 to 1.5 minutes. Longer priming intervals in the range of 3 to 4 minutes were previously described with the use of rocuronium priming.‘ag In the present study, significant improvement in the intubating conditions was observed in the clinical phase. The difference in intubating conditions between the mechanomyographic and clinical groups may appear surprising. However, the sequence of events during the induction period was different in the two phases. The priming sequence in the mechanomyographic studies is usually modified so that induction of anesthesia precedes the use of peripheral nerve stimulation. Neuromuscular blockers are only given after stabilization of control twitch height. Minimal anesthetics are used during the twitch stabilization period to mimic rapid-sequence induction of anesthesia and to avoid possible effects of inhalation drugs on the onset time and the intubating conditions. Therefore, at the time of intubation, anesthetic depth may be inadequate to provide optimum intubating conditions. This was probably the case in previous studies,‘,r2 as well as in the second phase of the present study. In the second mechanomyographic phase of this study, a single induction dose of propofol was given and N,O was the only anesthetic used during the twitch stabilization period. Induction-intubation intervals were approximately eight to nine minutes (twitch stabilization time t priming interval + onset of intubating dose). The initial distribution halflife of a single bolus dose of propofol is in the range of two to three minutesi Significant reductions in anesthetic depth may have occurred during the relatively long induction-intubation interval and may account for the high incidence of inadequate intubating conditions in the second phase of this study. In contrast, in the clinical phase, normal doses of induction drugs and neuromuscular blockers were administered in a standard clinical sequence. Mechanical recording of adductor pollicis response was omitted and the shortest priming interval (one minute) was used. This allowed for the conduct of a real rapidsequence induction. The induction-intubation interval was reduced and adequate depth of anesthesia was probably maintained at the time of intubation. Therefore, good to excellent intubating conditions were obtained in 80% to 90% of patients. Subjective muscle weakness is a distressing symptom frequently observed in awake patients during the priming interval. Donati14 suggested that the incidence of muscle
Priming with rocuronium: Abdulatifet
weakness could be minimized with the use of a priming dose equivalent to 10% of the ED,, of a neuromuscular blocking drug. However, Storella and colleaguesi emphasized the fact that adjustments to priming doses cannot substantially reduce the weakness associated with priming without also slowing the onset of full paralysis. The size of the priming dose of rocuronium used in this study was similar to that used by Foldes et al.’ The use of this dose level of rocuronium reduced the priming interval to one minute, during which patients were anesthetized and thus did not complain of any symptom of muscle weakness. This is a new approach to the management of subjective muscle weakness during the priming sequence. The total doses of nondepolarizing neuromuscular blocking drugs used in this study were equipotent and approximately equivalent to 2 x ED,5.16S” Bolus doses of rocuronium and atracurium were associated with comparable duration of action. In contrast, rocuroniumatracurium mixtures were associated with a longer duration of action. This finding may indicate a synergistic type of drug interaction between steroids and benzylisoquinolines. Synergistic interaction has been previously reported with rocuronium-mivacuriumi’ and vecuroniumatracuriumlg mixtures. We conclude that uniformly good to excellent intubating conditions are obtained only with succinylcholine. Priming doses of rocuronium 0.1 mg/kg reduce the priming interval to one minute, accelerate the onset time of intubating doses of atracurium, allow early induction of anesthesia, and eliminate symptoms of muscle weakness. When a rapid-sequence induction is required and atracurium is the drug of choice, a priming dose of rocuronium followed one minute later by an intubating dose of atracurium will be associated with an onset time and intubating conditions comparable with succinylcholine.
References 1. Donati F: Onset of action of relaxants. Can JAnaesth 1988;35:(3 (Pt Z)):S52-8. 2. Naguib M, Gyasi HK, Abdulatif M, Absood G: Rapid tracheal intubation with atracurium-a comparison of priming intervals, Can Anaesth Sot J 1986;33:150-6. 3. Taboada JA, Rupp SM, Miller RD: Refining the priming principle for vecuronium during rapid-sequence induction of anesthesia. Anesthesiology 1986;64:243-7.
al.
4. Mirakhur RK, Lavery GG, Gibson FM, Clarke RS: Intubating conditions after vecuronium and atracurium given in divided doses (the priming technique). Acta Anaesthesiol Scund 1986;30:347-50. 5. Mahajan RP, Hennessy N, Aitkenhead AR Effect of priming dose of vecuronium on lung function in elderly patients. Anesth An&g 1993;77:1198-1202. 6. Musich J, Walts LF: Pulmonary aspiration after a priming dose of vecuronium. Anesthesiology 1986;64:517-9. 7. Wierida JM, Kleef UW, Lambalk LM, Rloppenburg WD, Agoston S: The pharmacodynamics and pharmacokinetics of Org 9426, a new nondepolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. CunJ Anaesth 1991;38:430-5. 8. Naguib M: Different priming techniques, including mivacurium, acclerate the onset of rocuronium. Can JAnaesth 1994;41:902-7. 9. 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. 10. Fiset P, Balendran P, Bevan DR, Donati F: Nitrous oxide potentiates vecuronium neuromuscular blockade in humans. Can JAna&h 1991;38:866-9. 11. Fahey MR, Morris RB, Miller RD, Sohn YJ, Cronelly R, Gencarelli P: Clinical pharmacology of ORG NC 45 (Norcuron) : a new nondepolarizing muscle relaxant. Anesthesiology 1981;55:6-11. 12. Naguib M, Abdulatif M, Gyasi HE, Absood GH: Priming with atracurium: improving intubating conditions with additional doses of thiopental. An&h Analg 1986;65:1295-9. 13. Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ: Disposition of propofol in patients undergoing surgery. A comparison in men and women. Br JAnaesth 1986;58:1075-9. 14. Donati F: The priming saga: where do we stand now? Can JAnaesth 1988;35:1-4. 15. Storella RJ, Jaffe J, Mehr E, Rosenberg H: In vitro investigation of the priming principle for rapid neuromuscular block. BrJAnaesth 1989;62:478-82. 16. Belmont MR, Maehr B, Wastila WB, Savareseg: Pharmacodynamits and pharmacokinetics of benzylisoquinolinium (curare like) neuromuscular blocking drugs. Anesthesiol CZin N Am 1993;ll: 251-81. 17. Ducharme J, Donati F: Pharmacodynamics and pharmacokinetics of steroidal muscle relaxants. Anesthesiol Clin N Am 1993;11:283307. 18. Naguib M: Neuromuscular effects of rocuronium bromide and mivacurium chloride administered alone and in combination. Anesthesiology 7994;81:388-95. 19. Gibbs NM, Rung GW, Braunegg PW, Martin DE: The onset and duration of neuromuscular blockade using combinations of atracurium and vecuronium. Anaesth Intensive Care 1991;19:96-100.
J. Clin. Anesth., vol. 8, August 1996
381
Rocuronium Priming of Atracurium-Induced Neuromuscular Blockade: The Use of Short Priming Intervals Mohamed Abdulatif, MD,* Abduhnohsin Al-Ghamdi, MD,? Mohga El-Sanabary, MD$
Department of Anesthesia, Faculty of Medicine, Cairo University, Cairo, Egypt; Department of Anesthesia, King Faisal University, Al-Khobar, Saudi Arabia.
*Associate Professor t.Assistant Professor ~Lecturer Address correspondence to Dr. Abdulatif at the Department of Anesthesiology, King Fahad Hospital of the University, M-Khobar 31952, P.O. Box 40081, Saudi Arabia. Received for publication July 6, 1995; revised manuscript accepted for publication November 7. 1995.
Study Objective: To evaluate the effects of p riming doses of rocuronium on the duration of priming interval and on the outcome ofpriming sequence using rocuronium-atracurium combination. Design: Three phase, randomized, controlled study. Setting: Inpatient anesthesia in a university hospital. Patients: 144 ASA physical status I and IIpatients, 19 to 57 years of age, weighing 50 to 90 kg, and undergoing low-risk elective surgery. Interventions: Phase I, two equal grou;bs (n = 12) of adult patients anesthetized with propofol, fentanyl, and nitrous oxide (N,O), received a priming dose of rocuronium 0.1 mg/kg or vecuronium 0.015 mg/kg. Phase II included six equal groups (n = 12): Groups 1, 2, and 3 received a priming dose of rocuronium 0.1 mg/kg and atracurium 0.42 mg/kg for intubation. The priming intervals were, respectively, 1, 1.5, or 2 minutes in Groups 1, 2, and 3. Groups 4, 5, and 6 received, respectively, a bolus dose ofrocuronium 0.6 mg/kg atracurium 0.5 mg/kg, or succinylcholine 1 mg/kg. Intubation was performed at maximum block. Phase III included four equal groups {n = 12). A ptiming dose of rocuronium 0.1 mg/kg (Group 1) or a placebo (Groups 2, 3, and 4) was given to awake patients. Anesthesia was induced during the one-minute priming interval. Intubating doses of atracum’um 0.42 mg/kg, rocuronium 0.6 mg/kg, atracurium 0.5 mg/kg, or succinylcholine 1 mg/kg were given to Groups 1, 2, 3, and 4, respectively. Intubation was attempted 1 minute after intubating doses were administered. Measurements and Main Results: Add&or pollicis response to train-of-four stimulation was recorded mechanically in Phases I and II only. The priming interval after rocuronium 0.1 mg/kg was in the range of 1 to 2 minutes. Priming doses of rocuronium resulted in signijcant acceleration in the onset time of intubating doses of atracurium, iwespective of the duration of the priming interual. The onset times [mean (SD)] following rocuronium-atracurium sequence in Groups 1, 2, and 3 were, respectively, 67 (17), 73 (14), and 66 (18) seconds and were comparable with the onset of bolus dosesof rocuronium and succinylcholine. In Phase II, good to excellent intubating conditions were obtained in 41% to 58% of patients included in Groups 1 through 5. Excellent to good intubating conditions were obtained in all patients (100%) who received succinylcholine. In Phase
Journal of Clinical Anesthesia 8:376-381, 1996 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0952~8180/96/$15.00 PI1 SO952-8180(96)00078-5
Priming with rocuronium: Abdulatif et al.
III, good to excellent intubating conditions were obtained in 91% of patients who received rocuronium-atracurium sequence. Symptoms of muscle weakness were not reported. Conclusions: Priming doses of rocuronium 0.1 mg/kg reduce the priming interval to 1 minute, allow early induction of anesthesia, eliminate patient discomfort, and accebzrate the onset time of atracurium with i&abating conditions comparable with sucn’nylcholine and rocuronium.
Keywords: Intubation: relaxants: rocuronium, priming principle.
endotrachial; atracurium,
neuromuscular pharmacodynamics:
cations with known or suspected effects on neuromuscular transmission. All patients were premeditated with oral diazepam 10 mg, given approximately 90 minutes before surgery. In the operating room, lactated Ringer’s solution with 5% dextrose was commenced intravenously (IV) before induction of anesthesia. The present study was conducted in three phases. In the first two phases, neuromuscular blockade was monitored with the use of a force displacement transducer and neuromuscular blockers were administered after induction of anesthesia. The third phase examined the clinical relevance of the data obtained in Phases I and II.
Introduction
Phase I Mechanomyogw@hic Study
Rapid sequence induction of anesthesia should be carefully performed, with special attention to the possibility of hypoxia and aspiration of gastric contents. The time-delay between inducing anesthesia and securing the airway should be considered a danger period, which should be shortened as much as possible.’ With the use of the priming technique to accelerate the onset of atracurium or vecuronium, a priming interval of 3 to 5 minutes is usually required.2Z3 During this relatively long priming interval, awake patients may suffer from distressing symptoms of muscle weakness, eg, blurred vision, dysphagia, and respiratory embarrassment.4Z5 The risk of pulmonary aspiration also may increase.6 Rocuronium bromide is a new, intermediate-acting neuromuscular blocking drug with a rapid onset of action.’ Priming doses of rocuronium recently have been used to accelerate the onset time of intubating doses of rocuronium and mivacurium.8 Naguib’ suggested that the rapid onset of rocuronium may make it the drug of choice with the priming technique. However, the possible advantages of the rapid onset of rocuronium on the priming sequence were not evaluated. The aim of the present study was to examine the hypothesis that the rapid onset of rocuronium may reduce the priming interval. The effects of priming doses of rocuronium on the onset time and intubating conditions following intubating doses of atracurium were also evaluated.
The objective of this phase of the study was to examine the time course of action of priming doses of rocuronium to choose the spectrum of potentially effective priming intervals to be subsequently evaluated in Phase II. Rocuronium was compared with the slower acting analogue vecuronium. Twenty-four patients were included in this phase of the study. Anesthesia was induced in all patients with fentany12 pg/kg and propofo12.5 to 3 mg/kg. An appropriately sized laryngeal mask was used to maintain the airway. Anesthesia was then maintained with nitrous oxide (N,O) 70% in oxygen (0,) and additional doses of propofol as required. Ventilation was controlled to maintain normocapnia [end-tidal CO, partial pressure (P,,CO,) 35 to 40 mmHg] . Nasopharyngeal temperature was monitored and maintained at a level of 35.5”C to 37°C. Arterial blood pressure, ECG, O,% saturation, concentrations of N,O and P&O, were continuously monitored by a Cardiocap II monitor (Datex Instrumentarium Corporation, Helsinki, Finland). After induction of anesthesia, the ulnar nerve was stimulated at the wrist using supramaximal square pulses of 0.2 ms duration, delivered in a train-of-four (TOF) sequence at 2 Hz. The TOF pattern of nerve stimulation was automatically repeated every 10 seconds, using a Myotest peripheral nerve stimulator (Biometer International, Odense, Denmark). The resulting contractions of the adductor pollicis muscle were recorded using a force displacement transducer and a neuromuscular function analyzer (Myograph 2000, Biometer International, Odense, Denmark). Preload tension on the thumb was maintained at 300 g throughout the investigation. After stabilization of twitch height recording, patients were randomly allocated via closed envelope to one of two equal groups (n = 12) according to the type of neuromuscular blocking drug. Patients in Group 1 received one single IV bolus of rocuronium 0.1 mg/kg while patients in Group 2 received vecuronium 0.015 mg/kg. These priming doses of rocuronium and vecuronium are equipotent and are equivalent to approximately one-third the ED,,.‘*l’ The effect of these doses on the first twitch height (T,) and on the TOF ratio (fractional height of the fourth to the first response in the TOF sequence T4/T1) was continuously recorded until the development of maximum block.
Materials
and Methods
One hundred and forty-four ASA physical status I and II male and female adult patients aged 19 to 57 years (mean 32.6 yrs) and weighing 50 to 90 kg [mean 69 (SD 9.4) kg], were enrolled in this study. All patients were undergoing low-risk, elective surgery. The study was approved by the King Fahad University Hospital Ethics Committee, and all patients gave written informed consent. The following patients were excluded: those with asthma, those at high risk of aspiration and those in whom difficult intubation was anticipated. We also excluded from the study any patient suffering from cardiac, vascular, respiratory, hepatic, renal, or neuromuscular disorder, and those receiving medi-
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Anesth.,
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1996
377
Original Contributiwu
Maximum block was defined as the point at which no further decrease was observed in the evoked response of the adductor pollicis muscle to three consecutive stimuli. This phase of the study was terminated at this stage and subsequent anesthetic management was continued as appropriate for surgery. The following parameters were determined for each patient: (1) twitch stabilization time: the time interval in minutes between induction of anesthesia and the development of stable twitch height recordings; (2) time interval between the end of injection of the priming dose of neuromuscular blocking drug and the first appreciable fade in the evoked response (lag time); (3) time required for the development of maximum block; and (4) T, and TOF ratio at maximum block.
Phase II Mechanomyographic Study Seventy-two patients anesthetized and monitored as in Phase I were included. During the twitch stabilization period, anesthesia was maintained with 70% N,O in 0, delivered via a face mask. After stabilization of twitch height recordings, patients were randomly allocated to one of six equal groups (n = 12)) according to the type of neuromuscular blocking drug, its method of administration, and the duration of the priming interval. Groups 1, 2, and 3 received a priming dose of rocuronium 0.1 mg/kg followed by an intubating dose of atracurium 0.42 mg/kg. The priming intervals were, respectively, 1, 1.5, or 2 minutes in Groups 1, 2, and 3 (Table I). These priming intervals were selected in view of the results obtained in Phase I. Groups 4, 5, and 6 received single bolus doses of rocuronium 0.6 mg/kg, atracurium 0.5 mg/kg, or succinylcholine 1 mg/ kg, respectively. Saline placebo injections preceded the administration of intubating doses of neuromuscular blocker in Groups 4, 5, and 6. Endotracheal intubation was performed in all patients by the same experienced anesthetist at maximum block. Intubating conditions (Table 2) were evaluated by an observer who was unaware of the patient’s group. No additional doses of propofol or fentanyl were given before endotracheal intubation. After intubation, anesthesia was maintained with 70% N,O in 02, incremental doses of fentanyl, and a continuous infusion of propofol. The following parameters were determined for all pa-
Table 1.
Priming interval (h)
Primiig relaxant (WW
1
Rocuronium 0.1 Rocuronium 0.1 Rocuronium 0.1
1.5 2
-
-
1
*Significantly different from other groups. 378
J.
Grading of Intubating Conditions
Score 0
1 2 3
Intubating
Adapted from Fahey et al.”
tients: (1) twitch stabilization time, as in Phase I, (2) T, height and TOF ratio at the time of administration of the intubating dose of neuromuscular blocking drugs, (3) onset of block: the time interval between the end of injection of the intubating dose and the development of maximum block, and (4) time required for 10% spontaneous recovery of T,.
Clinical Study Forty-eight patients were included in this part of the study. A rapid-sequence induction of anesthesia was used. Patients were randomly allocated to one of four equal groups (n = 12) according to the type and the method of administration of neuromuscular blocking drugs (Table 3). A priming dose of rocuronium 0.1 mg/kg or a placebo was administered to awake patients after preoxygenation with 100% 0, for 3 minutes. Patients were informed about the possible consequences of the priming dose such as diplopia, heaviness in the eye lids, dysphagia, or difficulty in breathing. They were requested to report the occurrence of any of these symptoms before loss of consciousness. Based on the results of Phase II, a one-minute priming interval was used in the clinical part of this study. This brief priming interval was used for the induction of anesthesia using fentanyl 2 pg/kg and propofol 2.5 to 3 mg/ kg. Cricoid pressure was applied by an assistant just after the loss of verbal contact with patients. Group 1 patients received intubating doses of atracurium 0.42 mg/kg.
Clin. Anesth., vol. 8, August 1996
De.gree of block before intubating doses of relaxants Tl
(%)
81 (9) 71 (19) 69 -
(22) -
conditions
Cords abducted, good visualization, no patient movement Cords abducted, good visualization, diaphragmatic movement with intubation Cords slightly adducted, fair visualization, coughing with intubation Cords adducted, difficult visualization, gross body movements, and coughing with intubation
Priming Parameters and Neuromuscular Data in Different Mechanomyographic
Group (n = 12)
2 3 4 5 6
Table 2.
TOF (%) 75 (9) 54 (17) 48 (21)" - - - -
Groups [mean (SD) I
Onset time kc)
Intubating relaxant (mdkg)
Atracurium Atracurium Auacurium Rocuronium Atracurium Succinylcholine
0.42 0.42 0.42 0.60 0.50
1.00
67 73 66 56 114 57
(17) (14) (18) (12) (29)$ (17)
Tl
(10%) (mW
45 45 48 30
(S)* (6)* (4)"
(7)
28 (8) 8.4 (2)*
Primingwith rocuronium: Abdulatif& al. Table 3.
Priming Parameters and Intubating Conditions in Different Mechanomyographic Mechunomyographic
Groups
Priming Group (n = 12)
Priming relaxant @&it)
1
Rocuronium 0.1 Rocuronium 0.1 Rocuronium 0.1 -
2 3 4 5 6
interval (mm
1 1.5 2 -
and Clinical Groups
Intubation Intobating relaxant (mdkg)
Atracurium Atracurium Atacurium Rocuronium Atracurium Succinylcholine
0.42 0.42 0.42 0.60 0.50 1.00
Score
% of good to excellent intobating conditions
0
1
2
3
1
6
6 4 4 6 4 6
5 7 4 4 5 0
0 0 3 I 2 0
6 5 2 9
5 5 2 3
1
0
91”
2 3 0
0 5 0
83” 33 100”
1 1
1 1
58 41 41 58 41 100*
Clinical Groups
1 2 3 4 *Significantly
Rocuronium 0.1 different
1 -
Atracurium Rocuronium Atracurium Succinylcholine
0.42 0.60 0.50 1.00
from other groups.
Groups 2, 3, and 4 received, respectively, single bolus intubating doses of rocuronium 0.6 mg/kg, atracurium 0.5 mg/kg, or succinylcholine 1 mg/kg. Intubation was attempted in all patients one minute after the administration of the intubating dose of neuromuscular blocking drug, Intubating conditions were evaluated as in Phase II. Oxygen saturation was continuously monitored during induction and was recorded at the time of intubation. After the data were recorded, the anesthetist in charge of the case was informed about the relaxant(s) given so that he/she could plan the remainder of the anesthetic. Assessment of neuromuscular transmission, based on visual observation of the response of the hand muscles to ulner nerve stimulation, was started only after intubation. Statistical analyses were performed on the neuromuscular data by unpaired Student’s t test, one-way analysis of variance (ANOVA), and Student-Newman-Keuls test for multiple comparisons, as appropriate. Intubating conditions were compared with Kruskall-Wallis and chi-square tests. A p-value less than 0.05 was considered statistically significant. Results were expressed as means (SD).
Results Phase I Mechanomyographic Study The time required for stabilization of twitch height recording was 6.4 (1.5) minutes. Priming doses of rocuronium and vecuronium produced similar degrees of block in the first twitch and in the TOF response, However, the time course of action of rocuronium was significantly shorter than that of vecuronium. Appreciable degrees of neuromuscular blockade were evident after a lag time of 45 (12) and 115 (48) seconds following priming doses of rocuronium and vecuronium, respectively (p < 0.01). The times required for the development of maximum block following rocuronium and vecuronium were, respectively, I48
(21) and 312 (45) seconds (p < 0.01). Two minutes after the administration of the priming dose of rocuronium, T, and TOF ratio were ‘74.8% (16%) and 56% (14%)) respectively. These values were not statistically different from the T, and TOF ratio recorded at maximum block (Figure 1).
Phase II Mechanomyographic Study Twitch stabilization time was similar to Phase I. Priming doses of rocuronium resulted in significant fade in T, and in TOF response, before the administration of intubating doses of neuromuscular blocking drugs. The magnitude of first twitch depression (T,) was comparable in all priming groups (Groups 1,2, and 3). However, the fade in the TOF response was more pronounced in Group 3 patients who were allowed a two-minute priming interval (Table I). Complete suppression of TOF response (100% block) was obtained after intubating doses of neuromuscular blocking drugs in all patients. Priming doses of rocuronium resulted in significant acceleration in the onset time of subsequent intubating doses of atracurium irrespective of the duration of the priming interval. Bolus doses of atracurium were associated with the longest onset time
(Table 1). Good to excellent intubating conditions (scores of 0 and 1) were obtained in 41% to 58% of patients included in Groups 1 through 5. There were no statistically significant differences in the intubating scores between these groups. In contrast, excellent to good intubating conditions were obtained in all patients (100%) who received succinylcholine (Table 3). The duration of neuromuscular blockade in Groups 1, 2, and 3 who received rocuronium-atracurium sequence were, respectively, 45 (8), 45 (6), and 48 (4) minutes, and were significantly longer than other groups. Succinylcholine was associated with the shortest duration of action
(Table 1). J. Clin. Anesth., vol. 8, August 1996
379
Original Contributions 100 T
-
Tl Vecuronium
- 0 - Tl Rocuronium
90 --
-
T4 Vecuronium
- . - T4 Rocuronium
E .o 8O -H “0 !g 70 -5 E .P 2 60-F
*
‘.
\
. . -. * *
50 --
44-l
: : : : f : : : ( : : : : I 0 0.5 1.5 2.5 3.5 6.5 4.5 5.5 Time (minutes)
Figure 1. Time course of action and pattern of first twitch (T,) and train-of-four (TJ fade following priming doses of rocuronium and vecuronium. Error bars were omitted for the sake of clarity. *Significantly different compared with vecuronium group.
Clinical Study Priming doses of rocuronium, followed one minute later by intubating doses of atracurium (Groups I), were associated with good to excellent intubating conditions in 91% of patients (Table 3). These were comparable to intubating conditions obtained with bolus doses of rocuronium and succinylcholine. Intubating conditions in clinical group 1 were significantly better than in the mechanomyographic group who received the same doses of neuromuscular blocking drugs separated by a similar priming interval (mechanomyographic Groups 1). None of the patients reported any symptom of subjective muscle weakness before losing consciousness. Oxygenation was well maintained in all patients with a mean 0, saturation of 98.2 (1.3)% at the time of intubation.
In the present study, analysis of the time course of action of priming doses of rocuronium demonstrated that appreciable fade in the adductor pollicis response was detectable at 0.75 minutes, with a maximum block at 2.5 minutes. The degree of neuromuscular blockade recorded 380
J. Clin. Anesth., vol. 8, August 1996
after 2 minutes was not different from that obtained at maximum block. This finding implies that with the use of priming doses of rocuronium, effective neuromuscular block is present after a priming interval of 1 minute, and waiting more than 2 minutes is unnecessary. In the second phase of this study, priming doses of rocuronium significantly reduced the onset time of intubating doses of atracurium. The magnitude of this reduction reached about 50% and was not affected by the duration of the priming interval. However, the two-minute priming interval was associated with significantly lower TOF ratio at the time of administration of intubating doses (Table I). Therefore, the optimum priming interval after priming doses of rocuronium appears to be in the range of 1 to 1.5 minutes. Longer priming intervals in the range of 3 to 4 minutes were previously described with the use of rocuronium priming.‘ag In the present study, significant improvement in the intubating conditions was observed in the clinical phase. The difference in intubating conditions between the mechanomyographic and clinical groups may appear surprising. However, the sequence of events during the induction period was different in the two phases. The priming sequence in the mechanomyographic studies is usually modified so that induction of anesthesia precedes the use of peripheral nerve stimulation. Neuromuscular blockers are only given after stabilization of control twitch height. Minimal anesthetics are used during the twitch stabilization period to mimic rapid-sequence induction of anesthesia and to avoid possible effects of inhalation drugs on the onset time and the intubating conditions. Therefore, at the time of intubation, anesthetic depth may be inadequate to provide optimum intubating conditions. This was probably the case in previous studies,‘,r2 as well as in the second phase of the present study. In the second mechanomyographic phase of this study, a single induction dose of propofol was given and N,O was the only anesthetic used during the twitch stabilization period. Induction-intubation intervals were approximately eight to nine minutes (twitch stabilization time t priming interval + onset of intubating dose). The initial distribution halflife of a single bolus dose of propofol is in the range of two to three minutesi Significant reductions in anesthetic depth may have occurred during the relatively long induction-intubation interval and may account for the high incidence of inadequate intubating conditions in the second phase of this study. In contrast, in the clinical phase, normal doses of induction drugs and neuromuscular blockers were administered in a standard clinical sequence. Mechanical recording of adductor pollicis response was omitted and the shortest priming interval (one minute) was used. This allowed for the conduct of a real rapidsequence induction. The induction-intubation interval was reduced and adequate depth of anesthesia was probably maintained at the time of intubation. Therefore, good to excellent intubating conditions were obtained in 80% to 90% of patients. Subjective muscle weakness is a distressing symptom frequently observed in awake patients during the priming interval. Donati14 suggested that the incidence of muscle
Priming with rocuronium: Abdulatifet
weakness could be minimized with the use of a priming dose equivalent to 10% of the ED,, of a neuromuscular blocking drug. However, Storella and colleaguesi emphasized the fact that adjustments to priming doses cannot substantially reduce the weakness associated with priming without also slowing the onset of full paralysis. The size of the priming dose of rocuronium used in this study was similar to that used by Foldes et al.’ The use of this dose level of rocuronium reduced the priming interval to one minute, during which patients were anesthetized and thus did not complain of any symptom of muscle weakness. This is a new approach to the management of subjective muscle weakness during the priming sequence. The total doses of nondepolarizing neuromuscular blocking drugs used in this study were equipotent and approximately equivalent to 2 x ED,5.16S” Bolus doses of rocuronium and atracurium were associated with comparable duration of action. In contrast, rocuroniumatracurium mixtures were associated with a longer duration of action. This finding may indicate a synergistic type of drug interaction between steroids and benzylisoquinolines. Synergistic interaction has been previously reported with rocuronium-mivacuriumi’ and vecuroniumatracuriumlg mixtures. We conclude that uniformly good to excellent intubating conditions are obtained only with succinylcholine. Priming doses of rocuronium 0.1 mg/kg reduce the priming interval to one minute, accelerate the onset time of intubating doses of atracurium, allow early induction of anesthesia, and eliminate symptoms of muscle weakness. When a rapid-sequence induction is required and atracurium is the drug of choice, a priming dose of rocuronium followed one minute later by an intubating dose of atracurium will be associated with an onset time and intubating conditions comparable with succinylcholine.
References 1. Donati F: Onset of action of relaxants. Can JAnaesth 1988;35:(3 (Pt Z)):S52-8. 2. Naguib M, Gyasi HK, Abdulatif M, Absood G: Rapid tracheal intubation with atracurium-a comparison of priming intervals, Can Anaesth Sot J 1986;33:150-6. 3. Taboada JA, Rupp SM, Miller RD: Refining the priming principle for vecuronium during rapid-sequence induction of anesthesia. Anesthesiology 1986;64:243-7.
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4. Mirakhur RK, Lavery GG, Gibson FM, Clarke RS: Intubating conditions after vecuronium and atracurium given in divided doses (the priming technique). Acta Anaesthesiol Scund 1986;30:347-50. 5. Mahajan RP, Hennessy N, Aitkenhead AR Effect of priming dose of vecuronium on lung function in elderly patients. Anesth An&g 1993;77:1198-1202. 6. Musich J, Walts LF: Pulmonary aspiration after a priming dose of vecuronium. Anesthesiology 1986;64:517-9. 7. Wierida JM, Kleef UW, Lambalk LM, Rloppenburg WD, Agoston S: The pharmacodynamics and pharmacokinetics of Org 9426, a new nondepolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. CunJ Anaesth 1991;38:430-5. 8. Naguib M: Different priming techniques, including mivacurium, acclerate the onset of rocuronium. Can JAnaesth 1994;41:902-7. 9. 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. 10. Fiset P, Balendran P, Bevan DR, Donati F: Nitrous oxide potentiates vecuronium neuromuscular blockade in humans. Can JAna&h 1991;38:866-9. 11. Fahey MR, Morris RB, Miller RD, Sohn YJ, Cronelly R, Gencarelli P: Clinical pharmacology of ORG NC 45 (Norcuron) : a new nondepolarizing muscle relaxant. Anesthesiology 1981;55:6-11. 12. Naguib M, Abdulatif M, Gyasi HE, Absood GH: Priming with atracurium: improving intubating conditions with additional doses of thiopental. An&h Analg 1986;65:1295-9. 13. Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ: Disposition of propofol in patients undergoing surgery. A comparison in men and women. Br JAnaesth 1986;58:1075-9. 14. Donati F: The priming saga: where do we stand now? Can JAnaesth 1988;35:1-4. 15. Storella RJ, Jaffe J, Mehr E, Rosenberg H: In vitro investigation of the priming principle for rapid neuromuscular block. BrJAnaesth 1989;62:478-82. 16. Belmont MR, Maehr B, Wastila WB, Savareseg: Pharmacodynamits and pharmacokinetics of benzylisoquinolinium (curare like) neuromuscular blocking drugs. Anesthesiol CZin N Am 1993;ll: 251-81. 17. Ducharme J, Donati F: Pharmacodynamics and pharmacokinetics of steroidal muscle relaxants. Anesthesiol Clin N Am 1993;11:283307. 18. Naguib M: Neuromuscular effects of rocuronium bromide and mivacurium chloride administered alone and in combination. Anesthesiology 7994;81:388-95. 19. Gibbs NM, Rung GW, Braunegg PW, Martin DE: The onset and duration of neuromuscular blockade using combinations of atracurium and vecuronium. Anaesth Intensive Care 1991;19:96-100.
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