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ORIGINAL ARTICLE
Year : 2010  |  Volume : 4  |  Issue : 3  |  Page : 152-157

Cisatracurium in different doses versus atracurium during general anesthesia for abdominal surgery


Department of Anaesthesia, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Correspondence Address:
H M Atef
Department of Anaesthesiology, Faculty of Medicine, Suez Canal University, Ismailia
Egypt
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Source of Support: The Egyptian Ministry of High Education, Conflict of Interest: None


DOI: 10.4103/1658-354X.71571

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Date of Web Publication12-Oct-2010
 

  Abstract 

Background: Cisatracurium in clinical practice is devoid of histamine-induced cardiovascular effects. On the other hand, 2 ED 95 doses of cisatracurium (100 μg/kg) do not create satisfactory intubating conditions such as those seen with equipotent doses of atracurium. The recommended intubating dose of cisatracurium is 3 ED 95 . To understand this discrepancy better, we evaluated the potency and onset of atracurium and cisatracurium. Materials and Methods: The study designed as randomized controlled clinical trial to compare between atracurium (2ΧED 95 ) and different doses of cisatracurium (2ΧED 95 , 4ΧED 95 , 6ΧED 95 ) regarding onset time, duration of action, condition of intubation, hemodynamic effects, and sings of histamine release clinically. Sixty four patients were randomly assigned to one of four groups, the first group (group 1) received 2ΧED 95 dose of atracurium, group 2 received 2ΧED 95 dose of cisatracurium , group 3 received 4ΧED 95 dose of cisatracurium, while group 4 received 6ΧED 95 dose of cisatracurium. The Datex relaxograph (Type NMT-100-23-01, S/N: 37541) for neuromuscular monitoring was used. Results : HR, MABP was statistically significant increased post-intubation with administration of 2ΧED 95 dose of atracurium in group 1 and the same dose of cisatracurium in group 2 but 5-20 min later was not statistically significant with administration of 4ΧED 95 and 6ΧED 95 doses of cisatracurium in groups 3 and 4, respectively. Onset time was found to be significantly lower with 2ΧED 95 dose of atracurium than with the same dose of cisatracurium. At the same time, higher doses of cisatracurium (4ΧED 95 and 6ΧED 95 ) showed onset time and longer duration of action that was significantly lower than with atracurium and with lower dose of cisatracurium (2ΧED 95 ). Only 6ΧED 95 dose of cisatracurium showed statistically significant difference versus the atracurium dose with higher percentages of patients with excellent condition of intubation. 4ΧED 95 and 6ΧED 95 doses of cisatracurium were significantly better than 2ΧED 95 dose of cisatracurium. 2ΧED 95 dose of atracurium and 2ΧED 95 dose of cisatracurium were similar, while 4ΧED 95 and 6ΧED 95 doses of cisatracurium were significantly better than atracurium and 2ΧED 95 dose of cisatracurium. Conclusion: The same dose (2ΧED 95 dose) atracurium is more effective neuromuscular blocking agent than cisatracurium, while higher doses of cisatracurium 4ΧED 95 and 6ΧED 95 provide more effective, more rapid neuromuscular blocking with longer duration of action, stable hemodynamic status, and no associated signs of histamine release clinically.

Keywords: Cisatracurium, atracurium, different ED95 dose and neuromuscular monitoring


How to cite this article:
El-Kasaby A M, Atef H M, Helmy A M, El-Nasr M A. Cisatracurium in different doses versus atracurium during general anesthesia for abdominal surgery. Saudi J Anaesth 2010;4:152-7

How to cite this URL:
El-Kasaby A M, Atef H M, Helmy A M, El-Nasr M A. Cisatracurium in different doses versus atracurium during general anesthesia for abdominal surgery. Saudi J Anaesth [serial online] 2010 [cited 2020 Feb 22];4:152-7. Available from: http://www.saudija.org/text.asp?2010/4/3/152/71571


  Introduction Top


Muscle relaxants rapidly became a routine part of the anesthesiologist's drug arsenal. [1]

The neuromuscular blocking potency of cisatracurium (NIMBEX) is approximately three-fold that of atracurium besylate, the time to maximum block is up to 2 min longer for equipotent doses of NIMBEX compared to atracurium besylate. The clinically effective duration of action and rate of spontaneous recovery from equipotent doses of NIMBEX and atracurium besylate are similar. [2]

Although cisatracurium is more potent than the parent mixture (95% effective dose (ED 95 ) 0.05 mg/kg vs. 0.2 mg/kg), its pharmacodynamic profile is similar to that of atracurium, except for a reportedly slower onset. [3] Cisatracurium unlike atracurium is devoid of histamine-induced cardiovascular effects. On the other hand, 2 ED 95 doses of cisatracurium (100 ΅g/kg) do not yield satisfactory intubating conditions such as those seen with equipotent doses of atracurium. The recommended intubating dose of cisatracurium is 3 ED 95 . [4],[5]

Aim of the work

This study was designed to compare between atracurium (2ΧED 95 ) and different doses of cisatracurium (2ΧED 95 , 4ΧED 95 , 6ΧED 95 ) regarding onset time, condition of intubation, duration of action, hemodynamic effects, and signs of histamine release.


  Materials and Methods Top


The study was carried out as a comparative clinical trial on patients of both sexes underwent elective abdominal surgery in Suez Canal University Hospital in the routine surgical theaters.

Inclusion criteria

ASA I and ASA II patients aged from 20 to 65 years old, both sexes scheduled for abdominal surgeries of an anticipated duration of at least 1 h and half included in the study. Exclusion criteria were any disorder of the cardiovascular, hepatic, renal, or neuromuscular systems known from history or clinical examination. Patients in whom difficult intubation was expected: pregnant or lactating women and patients on medication known to interact with neuromuscular blocking drugs e.g. Antibiotics (aminoglycosides and tetracycline), antidepressants, anticonvulsants antiarrhythmics (calcium channel blockers and quinidine) and magnesium sulfate. The detectable difference between the means of the group using the onset of action (time from end of injection to 90% neuromuscular block) and it equals 0.7 minutes. [6]

The calculated sample is 16 per group with total sample size 64 for the four groups of the study.

The 64 patients were equally and randomly divided into four groups:

Group 1: atracurium for 16 patients with initial dose of 0.5 mg/kg (2ΧED 95 ).

Group 2: cisatracurium for 16 patients with initial dose of 0.1 mg/kg (2ΧED 95 ).

Group 3: cisatracurium for 16 patients with initial dose of 0.2 mg/kg (4ΧED 95 ).

Group 4: cisatracurium for 16 patients with initial dose of 0.3 mg/kg (6ΧED 95 ). Patients were randomly allocated using an online research randomizer ( http://www.randomizer.org/ ) into four equal groups.

The techniques were explained to patients including benefits and complications of each and written consent was taken. The patient's age, sex, ASA status, duration, and type of surgery were recorded. Patients were premedicated using 2 mg midazolam through IV route 20 min preoperatively.

Monitoring equipments (Datex-Ohmeda™) were attached to the patient including three leads ECG, non-invasive blood pressure, pulse oximetry, capnography, and temperature probe. The Datex relaxograph (Type-NMT-100-23-01, S/N: 37541) for neuromuscular monitoring. The first response (T 1 ) of the train of four (TOF) stimulation was the parameter, which used for the pharmacodynamic measurements. The hand, wrist and half of the forearm were wrapped with crepe bandage to avoid hypothermia. Patients were preoxygenated with 100% oxygen for 3 min.

General anesthesia was induced with fentanyl (1-1.5 ΅g/kg), followed 20 s later by propofol (2 mg/kg) intravenously. Anesthesia was maintained with a mixture of 50% N 2 O in O 2 and isoflurane (0.5%-1.5% vol%) and assisted ventilation. Neuromuscular monitoring was carried out after obtaining the control values by supramaximal stimulus (70 mA) from relaxograph (2 Hz/0.5 s; pulse width 0.2 ms) every 20s to stimulate the ulnar nerve via surface electrodes.

After a stable base line period of at least 5 min, the muscle relaxant was given for patients according to the previously mentioned initial doses for each group and injected intravenously within 5-10 s. After 2 min, endotracheal intubation was attempted using proper size tube (male: 8-9, female: 7-7.5) and the condition of intubation was assessed and recorded according to the following: [7]

  1. Excellent: Easy passage of the tube without coughing. Vocal cords relaxed and abducted.
  2. Good: Passage of the tube with slight coughing and/or bucking. Vocal cords relaxed and abducted.
  3. Poor: Passage of tubes with moderate coughing and/or bucking vocal cords moderately adducted.
  4. Not possible: Vocal cords not relaxed, tightly adducted.
The onset time was determined as the interval from the end of muscle relaxant injection until the maximal suppression of T 1 %.

Anesthesia was maintained with a mixture of 50% N 2 O in O 2, isoflourane (1-1.5 MAC), boluses of the muscle relaxant (10% of the initial dose) with 25% recovery of response to T 1 % and ventilation was controlled by the Datex-Ohmeda ventilator which will adjust end tidal CO 2 at (30-35 mmHg). Neuromuscular blockade after induction was monitored and recorded every 5 min by supramaximal train-of-four (TOF) stimuli.

The duration of the muscle relaxant (time from the end of injection of the drug until 25% recovery of T 1 %) was recorded.

Patients were monitored for any signs of histamine release clinically through skin changes graded as flush (if redness lasted> 120 s), erythema, or wheals [8] and presence of any hemodynamic changes or bronchospasm.

Intra-operative hemodynamic changes were continuously displayed on the monitor including: heart rate (HR), mean arterial blood pressure (MABP) every 5 min, oxygen saturation (SO 2 ), and end tidal CO 2 .

Body temperature was maintained between 35 and 37 o C by means of warmed IV fluids and warming blankets (body core temperature through nasopharyngeal probe and skin temperature probe).

At the end of operation with 25% recovery of T 1 %, reversal (induced recovery) was achieved by administration of neostigmine and atropine mixture (2.5 mg neostigmine: 1 mg atropine) through slow IV injection. TOF-ratio>0.9 was sufficient for safe extubation of the trachea.

Statistical methods

Data were processed using SPSS version 15 (SPSS Inc., Chicago, IL, USA). Quantitative data were expressed as means±SD while qualitative data were expressed as numbers and percentages (%). Student t test and ANOVA test were used to test significance of difference for quantitative variables (HR, BP) that follow normal distribution and chi square was used to test the significance of difference for qualitative variables. A probability value (P-value)<0.05 was considered statistically significant.


  Results Top


The studied patients were matched regarding age and sex with no statistically significant difference being recorded [Table 1].
Table 1: Demographic characteristics of the studied patients

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There was a statistically significant increase in HR, MABP post intubation when compared to baseline and postinjection of 2ΧED 95 dose of atracurium in group 1 and the same dose of cisatracurium in group 2. HR,MABP changes 5-20 minutes later were not statistically significant with administration of 4ΧED 95 and 6ΧED 95 doses of cisatracurium in groups 3 and 4, respectively [Table 2] and [Table 3].
Table 2: Heart rate changes before and after administration of atracurium or cisatracurium

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Table 3: Mean arterial blood pressure changes before and after administration of atracurium or cisatracurium

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Time onset was found to be significantly lower with 2ΧED 95 dose of atracurium than with the same dose of cisatracurium. At the same time, higher doses of cisatracurium (4ΧED 95 and 6ΧED 95 ) showed onset time that was significantly lower than with atracurium and with lower dose of cisatracurium (2ΧED 95 ). Regarding the duration of action, higher doses of cisatracurium (4ΧED 95 and 6ΧED 95 ) showed statistically significant longer duration of action than lower doses of cisatracurium and the atracurium (2ΧED 95 ) [Table 4].
Table 4: Neuromuscular blockade after administration of atracurium and cisatracurium

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Only 6ΧED95 dose of cisatracurium was statistically significant versus the atracurium dose with higher percentages of patients with excellent condition of intubation. 4ΧED 95 and 6ΧED 95 doses of cisatracurium were significantly better than 2ΧED 95 dose of cisatracurium. No one of the studied patients in the four groups been reported as not possible intubation. Assessment of vocal cords, 2ΧED 95 dose of atracurium and 2ΧED 95 and 4ΧED 95 doses of cisatracurium were similar while 6ΧED 95 dose of cisatracurium was significantly better than atracurium and 2ΧED 95 dose of cisatracurium [Table 5].
Table 5: Condition of intubation and vocal cords assessment as recoded after 2 minutes of administration of atracurium and cisatracurium

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No signs of histamine release were noted with any doses of cisatracurium, while it was noted with atracurium (2 cases; 1 case showed flush and the other case showed erythema).


  Discussion Top


All patients were assessed for hemodynamic state (heart rate, blood pressure), onset time, duration of action, and signs of histamine release clinically, condition of intubations, and vocal cords assessment.

The four groups of the study were matched regarding patients' age and sex.

Hemodynamic stability for both heart rate and mean arterial blood pressure were more evident among higher doses of cisatracurium (4ΧED 95 , 6ΧED 95 ).

There was a statistically significant increase in HR, MABP postintubation 120 s postinjection of the muscle relaxant when compared to baseline and postinjection of 2ΧED 95 dose of atracurium in group 1 and the same dose of cisatracurium in group 2 because of stress intubation and the patients were not fully relaxed. However, changes in HR and MABP 5-20 minutes later were not statistically significant with administration of 4ΧED 95 and 6ΧED 95 doses of cisatracurium in groups 3 and 4, respectively. Lien et al., [9] and Basta et al., [10] concluded that the maximal MABP and HR changes of patients receiving cisatracurium were small and similar to those observed in patients receiving two times the ED 95 of atracurium. In his study no patient developed a decrease in blood pressure >20% or an increase in heart rate >20% that was attributable to muscle relaxant administration. Signs of histamine release were shown in one patient in this study in the form of transient facial flushing after the administration of atracurium; however, this patient did not experience hypotension or tachycardia.

The onset time was determined as the interval from the end of muscle relaxant injection until the onset of the maximal suppression of T 1 and the duration of action of the muscle relaxant was defined as time from disappearance of TOF stimulation till 25% recovery of T 1 .

2ΧED 95 dose of atracurium had more rapid onset of action (with statistical significance) than the equivalent dose of cisatracurium (2ΧED 95 ). But higher doses of cisatracurium (4ΧED 95 and 6ΧED 95 ) were found to be statistically significant more rapid onset of action and longer duration of action than 2ΧED 95 dose of both atracurium and cisatracurium. Bluestein and colleagues, [11] studied 80 ASA physical status I or II, 18 - 70 years of age whom were randomly assigned to four groups (A-D). Group A received cisatracurium 0.1 mg/kg (2ΧED 95 ), group B received atracurium 0.5 mg/kg (2ΧED 95 ). Patients in group C and group D were treated with cisatracurium 0.2 mg/kg (4ΧED 95 ) and 0.15 mg/kg (3ΧED 95 ), respectively. They assessed the mean time of onset, mean time of clinically effective duration, and condition of intubation. As regarding the mean time of onset and mean time of clinically effective duration there results were in accordance with ours. They reported that increasing the initial dose of cisatracurium (from 0.1 to 0.15 and 0.2 mg/kg), decreased the mean time of onset (from 4.6 to 3.4 and 2.8 min, respectively) and increased the mean time of clinically effective duration (45 to 55 and 61 min, respectively). Mellinghoff et al., [3] studied 80 patients randomized to receive either cisatracurium (n=40) or atracurium (n=20) and compared the time course of neuromuscular block. Results obtained by Mellinghoff et al., [3] were similar to our results. They estimated that onset times were 3.1±1.0 min with cisatracurium and 2.3±1.1 min with atracurium (P=0.008). After the infusion, the spontaneous recovery intervals were 25-75% of 18±11 min and 18±8 min for cisatracurium and atracurium (P=0.896) [Table 6].
Table 6: Histamine release among the studied patients

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As regards the condition of intubation in our study, it was estimated that only 6ΧED 95 dose of cisatracurium showed a statistically significant difference versus the atracurium dose with excellent condition of intubation. 4ΧED 95 and 6ΧED 95 doses of cisatracurium were significantly better than 2ΧED 95 dose of cisatracurium. There was not any case of not possible intubation among the four studied groups. The assessment of vocal cords, 2ΧED 95 dose of atracurium, and 2ΧED 95 dose of cisatracurium were similar, while 4ΧED 95 and 6ΧED 95 doses of cisatracurium were significantly better than atracurium and 2ΧED 95 dose of cisatracurium. Results found by Bluestein et al., [11] were consistent with our results. They reported that intubation conditions were good or excellent in over 90% of patients in all treatment groups (2 min after approximately 2ΧED 95 doses of cisatracurium or atracurium and 1.5 min after 3Χ and 4ΧED 95 doses of cisatracurium).

Mandal [12] conducted a study in 60 adult patients of either sex, belonging to physical status ASA grade I or 11 to find out the minimum possible dose of cisatracurium for achieving excellent to good intubating conditions within 90 s of its administration under general anesthesia. Patients were divided into three groups according to their dosage schedule. After induction of anesthesia with the standardized method, group I (n=20) received 0.15 mg/kg, group II (n=20) received 0.20 mg/kg, and group III (n=20) received 0.25 mg/kg of cisatracurium. For each group laryngoscopy and intubation was tried at either 75 or 90s, thereby patients were further divided into six subgroups. Subgroup 'a' denotes the procedure at 75s and, 'b' denotes at 90s. For grading the intubating conditions, the ease of laryngoscopy, the position or movement of the vocal cords and the degree of coughing were evaluated. Excellent to good intubating conditions could be achieved only in group IIb (0.20 mg/kg at 90 s) and both subgroups (0.25 mg/kg at 7 5s and 90 s) in group III patients. Hence the minimum dose required to achieve excellent to good intubating conditions with cisatracurium is 0.20 mg/kg at 90 s after its administration. The adequacy of conditions for tracheal intubation is a function of several factors, such as the depth of anesthesia at the time of the intubation attempt and the level of neuromuscular block at the time of attempt. [13]

One of two intubating doses of cisatracurium may be chosen based on the desired time of intubation and the anticipated length of surgery. Doses of 0.15 mg/kg (3ΧED 95 ) and 0.2 mg/kg (4ΧED 95 ) of cisatracurium, as components of a propofol /nitrous oxide/oxygen induction intubation technique, may produce generally good or excellent conditions of intubation in 2.0 and 1.5 min, respectively. [14]

The cisatracurium dose of 0.15 mg/kg (3ΧED 95 ) is higher than the dose of atracurium 0.5 mg/kg (2ΧED 95 ) required to produce clinically acceptable intubation conditions after 120 s. However, this dose of cisatracurium still provides neuromuscular block of intermediate duration and following rapid administration not associated with histamine-mediated cardiovascular effects. [13]

No signs of histamine release were noted in any doses of cisatracurium while it was noted with atracurium (2 cases; 1 case showed flush and the other case showed erythema).

Signs of histamine release were shown in two patients with administration of 2ΧED 95 dose of atracurium in group 1, one patient in the form of flushing at the site of injection in the ventral aspect of the forearm but the patient did not experience hypotension or tachycardia and the other patient had shown transient erythema after the administration of atracurium and tachycardia only (an increase in heart rate<20% of base line) without any decrease in blood pressure.

As a benzylisoquinoline, atracurium has the potential for release of histamine. The syndrome becomes clinically evident when doses of 0.5 mg/kg (two times ED 95 ) or more are injected rapidly. [10]

When plasma histamine levels increase to over 1000 pg/ml, a transient decrease in blood pressure, together with facial erythema, may be noted. The phenomenon of histamine release may be shifted to the right by slower injection from 30 to 60 s. [10]

Combined H 1 and H 2 receptors blockade effectively prevents the cardiovascular manifestation of histamine release. Hosking et al., have treated patients with diphenylhydramine 1 mg/kg and cimetidine 4 mg/kg was given intravenously 30 min before giving a very large dose of atracurium (1.5 mg /kg or six times ED 95) , and the atracurium-induced decrease in mean arterial blood pressure was reduced to 30 mmHg (37%below baseline) in treated patients. [15] Despite a 10 to 20-folds increase in plasma histamine levels atracurium is non-vagolytic and does not block autonomic ganglia. [16]

We can conclude that at the same dose (2ΧED 95 dose) atracurium is more effective neuromuscular blocking agent than cisatracurium, while higher doses of cisatracurium provide more effective, more rapid neuromuscular blocking with longer duration of action, stable hemodynamic status, and no associated signs of histamine release clinically.

 
  References Top

1.Kleinman W, Nitti GJ, Nitti JT, Raya J. Neuromuscular blocking agents. In: Morgan GE, Mikhail MS, Murray MJ, editors. Clinical anesthesiology, 4 th Ed. New York: Lange Medical Books/McGraw Hill Medical publishing Division; 2006.P. 205.  Back to cited text no. 1      
2.Kleinman W, Nitti GJ, Nitti JT, Raya J. Neuromuscular blocking agents. In: Morgan GE, Mikhail MS, Murray MJ, editors. Clinical anesthesiology, 4 th ed. New York: Lange Medical Books/McGraw Hill Medical publishing Division; 2006.p.221.  Back to cited text no. 2      
3.Mellinghoff H, Radbrush L, Diefenbach C, Buzello W. A comparison of cisatracurium and atracurium: onset of neuromuscular block after bolus injection and recovery after subsequent infusion. Anaesth Analg 1996;83:1072-5.  Back to cited text no. 3      
4.Kirov K, Motamed C, Decailliot F, Behforouz N, Duvaldestin P. Comparison of the neuromuscular blocking effect of cisatracurium and atracurium on the larynx and the adductor pollicis.Acta Anaesth Scand 2004;48:577-81.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Nogueira CM, Sudo GZ, Sudo RT. Hemodynamic effects of atracurium and cisatracurium and the use of diphenhydramine and cimetidine. Rev BrasAnestesiol 2010;60:1.  Back to cited text no. 5      
6.Hermann M, Lukas R, Christoph D, Walter B. A comparison of cisatracurium and atracurium: onset of neuromuscular block after bolus injection and recovery after subsequent infusion. Anesth Analg 1996;83:1072-74.  Back to cited text no. 6      
7.Goldberg M, Larijani G, Azad S. Comparison of tracheal intubation conditions and neuromuscular blocking profiles after intubating dose of mivacurium chloride or succinylcholine in surgical outpatients. Anesth Analg 1989;69:93-9.  Back to cited text no. 7      
8.Doenicke A, Moss J, Lorenz W, Gottardis M. Are hypotension and rash after atracurium caused by histamine release? Anaesth Analg 1994;78:967-72.  Back to cited text no. 8      
9.Lien CA, Belmont MR, Abalos A. The cardiovascular effects and histamine-releasing properties of 51W89 in patients receiving nitrous oxide / opioid / barbiturate anesthesia. Anesthesiol 1995;82:1131-38.  Back to cited text no. 9      
10.Basta SJ, Ali HH, Savarese JJ.Clinical pharmacology of atracurium besylate: a new nondepolarizing muscle relaxant. Anaesth Analg 1992;61:723-29.  Back to cited text no. 10      
11.Bluestein LS, Stinson LW, Lennon RL, Wilson RM.Evaluation of cisatracurium, anew neuromuscular blocking agent for tracheal intubation. CAN J ANAESTH 1996;43:925-31.  Back to cited text no. 11      
12.Mandal P. Intubating Conditions after Cisatracurium Administration-A Dose Response Study in Adults. J Anaesth Clin Pharmacol 2002;18:147-51.  Back to cited text no. 12      
13.Belmont MR, Lien CA, Quessy S. The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiol 1995;82:1139 -45.  Back to cited text no. 13      
14.Schmautz E, Deriaz H, Vrillon M. Evaluation of 51W89 for endotracheal intubation in surgical patients during N 2 O/O 2 /propofol anesthesia. Anesthesiol 1994;81:1081.  Back to cited text no. 14      
15.Hosking MP, Lennon RL, Gronert GA. Combined H1 and H2 receptor blockade attenuates the cardiovascular effects of high dose atracurium for rapid sequence endotracheal intubation. Anaesth Analg 1988;67:1089-92.  Back to cited text no. 15      
16.Hughes R, Chapple DJ. The pharmacology of atracurium a new competitive blocking agent. Br J Anaesth 1981;53:131-44.  Back to cited text no. 16      



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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