The Lack of Histamine Release with Cisatracurium: A Double-Blind Comparison with Vecuronium

The Lack of Histamine Release with Cisatracurium: A Double-Blind Comparison with Vecuronium

Alfred Doenicke, MD*, Jens Soukup, MDt, Rainer Hoernecke, PhD*, and Jonathan Moss, MD, PhD$

*Institute of Anesthesiology, Ludwig Maximilians University of Munich, Munich, Germany; tDepartment of Anesthesia and Critical Care, Martin-Luther University, Halle, Germany; and #Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois

A prospective, randomized, double-blind study was performed in 62 patients (ASA Classes I and II) treated with either 0.15 or 0.25 mg/kg cisatracurium or 0.15 mg/kg vecuronium administered as a rapid bolus. We wished to determine whether the muscle relaxants caused cutaneous, systemic, or chemical evidence of histamine release. Six minutes after induction of anes- thesia with thiopental, patients received one of the mus- cle relaxants over 5 s. Plasma histamine levels were measured by radioimmunoassay after thiopental ad- ministration and 3 and 5 min after the administration of the relaxant. Additionally, plasma was assayed for tryptase, a marker of mast cell release. Cutaneous man- ifestations to both thiopental and the muscle relaxant were graded by an independent observer. Arterial blood pressure and heart rate were measured every

minute. Although systolic and diastolic blood pressure decreased and heart rate increased significantly after thiopental administration (P < O.OOOl), there were no further hemodynamic changes after either cisatra- curium or vecuronium. One patient who received 0.25 mg/kg cisatracurium exhibited a slight elevation in plasma histamine level 5 min after hemodynamic changes. Cutaneous signs of histamine release were noted in five patients after thiopental administration (flush in four, erythema in one), but no further cutane- ous reactions were observed after administration of either cisatracurium or vecuronium. We conclude that cis- atracurium and vecuronium do not cause systemic or cu- taneous histamine release. Tryptase levels showed no ev- idence of mast cell degranulation.

(Anesth Analg 1997;84:623-8)

C isatracurium (51W89), which has a IR-cis, l’R- cis configuration, is 1 of the 10 stereoisomers of atracurium (1). In previous clinical studies, ad-

ministration of this drug in doses up to 8 X the 95% effective dose (ED& for neuromuscular blockade was without important cardiovascular side effects or his- tamine release (2,3). The initial study of this com- pound was performed in generally healthy patients undergoingelective surgical procedures under nitrous oxide/opioid/barbiturate anesthesia, and patients re- ceived the drug after intubation. Two subsequent comparative studies with atracurium were performed in patients undergoing coronary artery surgery, but, in these studies, the cisatracurium was given 5 min after endotracheal intubation with succinylcholine (3) and at lower (2 X ED& doses (4). Therefore, we under- took a double-blind, controlled clinical trial to compare

This work was funded in part by Glaxo Wellcome. Accepted for publication November 20, 1996. Address correspondence and reprint requests to: Jonathan Moss,

MD, PhD, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637.

01997 by the International Anesthesia Research Society 0003.2999/97/55.00

the cardiovascular effects and histamine-releasing poten- tial of bolus doses 3 or 5 X the ED,, dose of cisatracurium with 3 X ED,, dose of vecuronium. The purposes of our study were to compare equipotent doses of vecuronium and cisatracurium for chemical, systemic, or cutaneous evidence of histamine release when given as an intrave- nous bolus 6 min after induction with thiopental.

Methods With the approval of our institutional review board and informed consent, 62 patients (ASA Classes I and II) undergoing elective surgery were randomly as- signed to one of three groups. All patients were pre- medicated orally with 2 mg lormetazepam 1 h before induction of anesthesia. After starting an intravenous catheter in one arm for drug and fluid administration and another in the contralateral arm for blood with- drawal, anesthesia was induced with thiopental 4-12 mg/kg and maintained with 30%-50% 0,, 30%- 50% N,O, and isoflurane 1.5%-2%. The variability in thiopental doses was contingent on the requirement to

Anesth Analg 1997;84:623-8 623

624 DOENICKE ET AL CISATRACURIUM AND HISTAMINE RELEASE

ANESTH ANALG 1997;84:623-8

induce and maintain apnea and unconsciousness. Six minutes after administration of thiopental, the pa- tients received either 0.15 mg/kg (n = 21), 0.25 mg/kg (n = 21) cisatracurium, or 0.15 mg/kg vecuronium (n = 20) as a rapid bolus administration (5 s). The muscle relaxant was administered by AD, who was also blinded as to its identity. Six minutes after the administration of the muscle relaxant, 0.1-0.2 pg fen- tanyl was administered, and the patients were trache- ally intubated. Fentanyl was given at this later time so as not to interfere with our assessment of the cutane- ous effects of the muscle relaxant (5). Heart rate and blood pressure were monitored every minute. Arterial blood pressure was recorded by periodic, noninvasive measurement by an oscillation method. Changes in arterial blood pressure or heart rate were considered clinically significant if they deviated 20% from prein- duction levels. Both the clinician and patient were blinded to the drug given. Changes in hemodynamics were recorded by another investigator blinded to the muscle relaxant given. Additionally, the independent observer (AD) assessed the presence of cutaneous manifestations of histamine release at each of the time periods at which samples for plasma histamine were recorded. Cutaneous manifestations were tabulated by the blind observer as previously described (6). Skin changes were graded as flush, constant redness (if longer than 120 s>, erythema, or wheals.

Samples for plasma histamine (5 mL) were with- drawn from a contralateral intravenous catheter 5 min before and 3 and 5 min after the administration of thiopental (1 min before muscle relaxant administra- tion), and 3 and 5 min after the muscle relaxant had been administered. Additionally, 5 mL of plasma was harvested for measurement of plasma tryptase, a marker of mast cell release (7), at baseline (10 and 1 min before), and 15 min and 120 mm after the administration of the muscle relaxant.

Plasma histamine was measured by radioimmunoas- say with appropriate internal standards (8). The sensi- tivity of this assay is approximately 10 pg/mL for bio- logical samples, with intra- and interassay variability of 8% and ll%, respectively. Changes in heart rate or blood pressure >20% of baseline were arbitrarily assigned as clinically significant; plasma histamine levels of >l ng/mL were considered significant measures of his- tamine release (9). Tryptase was measured using a ra- dioimmunoassay kit (Pharmacia, Piscataway, NJ) (7,lO). Values >l pg/L were considered abnormal. Data were analyzed by paired t-test and analysis of variance.

Results Figures l-4 compare the changes in heart rate and blood pressure after the administration of thiopental and each of the three muscle relaxants with preinduc- tion control values. Thiopental consistently induced a

Figure 1. Maximum changes in the systolic blood pressure and heart rate in patients 5 mm after the administration of thiopental. Each point represents one patient.

Figure 2. Maximum changes in the systolic blood pressure and heart rate in patients 5 min after the administration of cisatracurium (0.25 m&kg). Each point represents one patient.

modest but statistically significant hypotension and tachycardia (Fig. 5). Systolic blood pressure decreased from 129.9 t 14.0 mm Hg to 117.2 5 16.5 mm Hg; diastolic blood pressure decreased from 76.4 ? 11.8 mm Hg to 68.5 2 13.8 mm Hg; and heart rate increased from 81.7 + 16.2 bpm to 95.3 + 15.9 bpm (mean + SD) 5 min after the administration of thio- pental (P < 0.0001, paired t-test). Subsequent admin- istration of the muscle relaxant did not produce addi- tional significant change in either heart rate or blood

ANESTH ANALG 1997:84:623-8

DOENICKE ET AL 625 CISATRACURIUM AND HISTAMINE RELEASE

Systolic Blood Pressure

160

.

80 Baseline After Thiopental

Diastolic Blood Pressure

Baseline After Thiopental

Heart Rate 150

130

&ii0

p 90

70

50 l&--+-i Figure 3. Maximum changes in the systolic blood pressure and

heart rate in patients 5 min after the administration of cisatracurium (0.15 mg/kg). Each point represents one patient.

Changes Heart Rate [%] Baseline After Thiopental

Figure 5. Box plot depicting hemodynamic effects of thiopental on systolic and diastolic blood pressure (mm Hg) and heart rate @pm) 5 min after administration. This format presents the first and third quartiles as top and bottom of box, median as middle line, and 90th percentile as whiskers. Outlying points (>2 SD) are shown as open circles. Significant changes were detected in all three variables (P < 0.0001).

paired t-test and analysis of variance revealed no sig- nificant differences among the three groups. The plasma histamine level of one patient was 1133 pg/mL 5 min after large-dose cisatracurium, but only 215 pg/mL and 134 pg/mL before and 3 min after drug administration, respectively. However, there was no change in heart rate or systolic blood pressure accompanying the increased histamine level. There were no increases in plasma tryptase levels. Cutaneous signs of histamine release were noted in five patients after thiopental administration (flush in four patients, erythema in one), but no further cuta- neous reactions were observed after administration of the muscle relaxant.

Figure 4. Maximum changes in the systolic blood pressure and heart rate in patients 5 min after the administration of vecuronium (0.15 mg/kg). Each point represents one patient.

pressure. However, for each muscle relaxant, there were several patients who had significant cardiovas- cular changes. In the small-dose cisatracurium group, 8 of 21 patients, 2 of whom had hypotension, exhibited significant hemodynamic changes; in the large-dose cisatracurium group, 2 of 21 patients had significant tachycardia. In the group receiving vecuronium, 2 of 20 patients sustained clinically relevant hypotension, and 1 patient had clinically significant tachycardia.

Plasma histamine data for each drug are presented as a box plot in Figure 6A-C. Analysis of the data by

Discussion Our study largely confirms the findings of Lien et al. (2), although we used vecuronium as the standard against which cisatracurium would be compared. There were, however, several important differences in the way in which we performed the study. In the study by Lien et al. (2), anesthesia was induced with intravenous midazolam 20-100 pg/kg, fentanyl

626 DOENICKE ET AL ANESTH ANALG CISATRACURKJM AND HISTAMINE RELEASE 1997;84:623-8

A 12001 I

-1ooo- CISATRACURIUM 3 7% 800-

(0.15 mg/kg)

,a 0

0’ I

A-l A-2 A-3 A-4 A-S

B

12007 0 I -1000 - CISATRACURIUM 0 -

(0.25 mg/kg) on 800 -

,a

”

B-l B-2 B-3 B-4 B-5

C

1200 ’ I

-1OOo- VECURONIUM 1 h800- 0

(0.15 mg/kg)

,a

0’ v (? 1

C-l c-2 c-3 c-4 c-5

Figure 6. Box plot of plasma histamine (pg/mL). Samples were taken 5 min before thiopental (Al, Bl, Cl), 3 and 5 min after thiopental (A2, B2, C2 and A3, B3, C3), and 3 and 5 min after muscle relaxant (A4.84. C4 and A5. B5, C5) (A is cisatracurium 0.15 ma/kg. B is cisatracurium 0.25 m&/kg, and C is vecuronium 0.15 ma/k& This format presents the first and third quartiles as top and bottom of box, median as middle line, and 90th percentile as whiskers. Outlying points (>2 SD) are shown as open circles. No significant differences were detected among the three groups.

2-8 pg/kg, and thiopental l-10 m&/kg. We did not use opiates and midazolam before administration of muscle relaxants. Both studies used temporal separa- tion of the administration of the barbiturate or muscle relaxant to distinguish between the cardiovascular properties of the two drugs, although the times were different. Konstadt et al. (3) compared the cardiovas- cular effects of cisatracurium and vecuronium in pa- tients with coronary artery disease using a smaller dose of cisatracurium (2 X 95% effective dose [ED,&, and plasma histamine levels were not measured.

In clinical practice, it is common to administer the anesthetic and muscle relaxant in rapid sequence. As can be seen from the heart rate and blood pressure changes in Figures 1 and 5, hypotension and tachycar- dia often accompanied the administration of thiopen- tal. A modest but statistically significant decrease in systolic and diastolic blood pressure and increase in heart rate occurred 5 min after the administration of thiopental without an increase in plasma histamine, which suggests a direct effect of thiopental on the cardiovascular system. However, additional changes were relatively infrequent after the administration of either cisatracurium or vecuronium and were not due to histamine release (Figs. 2-4). The clinician who administers thiopental and a muscle relaxant concur- rently may attribute the resulting hypotension and/or tachycardia to histamine release. However, there is no chemical evidence for such release in our data, and there is a real likelihood that the effect is due to the administration of thiopental. Thus, an important con- clusion from our work is that the modest hypotension and tachycardia seen during a routine induction with thiopental and cisatracurium or vecuronium is much more likely to be due to the thiopental than to the muscle relaxant. We have previously suggested that much of the hemodynamic instability attributed to atracurium may be due to the thiopental (6).

Neither cisatracurium nor vecuronium caused in- creases in plasma histamine levels (Fig. 6A-C) or car- diovascular effects associated with systemic histamine release. In our previous study of vecuronium, we were unable to detect increases in plasma histamine (11). Although we did not observe significant histamine release with cisatracurium, we observed one patient with histamine release that marginally exceeded the 1 ng/mL threshold without accompanying cardiovas- cular signs, as did Lien et al. (2). Furthermore, the histamine level at the 3-min time point was within normal limits. This result could be an artifact or might suggest a somewhat delayed or attenuated release of histamine. In some patients receiving morphine and nalbuphine, histamine is released lo-15 minutes after the injection of the drug (12).

In addition to our inability to detect increases in plasma histamine levels after the muscle relaxant, we specifically looked for and failed to observe cutaneous manifestations after vecuronium or cisatracurium at either dose, which suggests a lack of histamine release from skin mast cells. Our finding is consistent with previous clinical observations. Although not specifi- cally quantifying rash within their methodology, Lien et al. (2) commented in their discussion that one pa- tient receiving atracurium experienced facial flushing without hypotension, tachycardia, or increased plasma histamine. Konstadt et al. (3) failed to observe cutaneous reactions at doses of 0.1 “g/kg. In contrast to what is seen with cisatracurium (3 x and 5 X ED,,),

ANESTH ANALG DOENICKE ET AL 627 1997;84:623-8 CISATRACURIUM AND HISTAMINE RELEASE

we observed a far greater incidence of cutaneous man- ifestations with bolus administrations with atra- curium (6) (2 X ED,,); in our prior study, 7 of 20 patients in the group receiving atracurium exhibited cutaneous manifestations. These did not occur in any of the 20 patients who were pretreated with H, and H, antihistamines. The lack of skin reactions with cisatra- curium is an important advantage to clinicians who may perceive such cutaneous manifestations as the harbinger of a systemic reaction (13).

In studies of other drugs, cutaneous effects of his- tamine release are manifested without an increase in plasma levels (6). Such differential release is well de- scribed in the allergy and anesthesia literature (14-19). Both the content of histamine and its releasability by drugs varies between cutaneous mast cells and those in the heart and lungs (15-19). Only cutaneous mast cells increase histamine at clinically relevant doses of

cisatracurium is primarily eliminated by the Hoff- mann elimination reaction. Thus, the choice between cisatracurium and vecuronium for procedures requir- ing intermediate duration of muscle relaxation in pa- tients, particularly those who are elderly or have renal impairment, may be determined by metabolism or elimination rather than by hemodynamic effects. Based upon our observations, we believe that cisatra- curium may be a viable alternative to vecuronium in patients with significant cardiovascular compromise and may be a better choice if there is a question of renal and liver impairment. Although it is possible that idiosyncratic or allergic reactions to this isomer of atracurium can occur, there appears to be little evi- dence for chemically induced histamine release, even at 5 X ED,, for neuromuscular block.

morphine (17). Fentanyl can also cause cutaneous re- actions (6). With muscle relaxants, a similar situation References prevails. Both vecuronium (20) and atracurium (14) can release histamine from selected mast cell popula- tions, although there is no chemical or clinical evi- dence of incrzased histamine levels with vecuronium (11,14). Given the functional and structural heteroge- neity of mast cells, the cutaneous manifestations at- tributable to atracurium may be a better marker of local histamine release than are plasma levels.

1. Belmont MR, Lien CA, Quessy ST, et al. The clinical neuromus- cular pharmacology of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1995;82: 1139-45.

2. Lien CA, Belmont MR, Abalos A, et al. The cardiovascular effects and histamine-releasing properties of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anes- thesiology 1995;81:1131-8.-

3. Konstadt SN. Reich DL. Stanlev TE III. et al. A two-center i comparison of the cardiovascular effects of cisatracurium (Nim- bexTM) and vecuronium in patients with coronary artery disease. Anesth Analg 1995;81:1010-4. We did not observe an increase in tryptase.

Tryptase, a protease that is coreleased with histamine from mast cells, serves as a marker for immunologic reactions and would not be expected to increase dur- ing chemically mediated reactions (7,20). Thus, our inability to observe elevations in tryptase was antici- pated. However, in the event of an elevation in plasma histamine or significant hemodynamic changes, we wanted to be able to distinguish between immuno- logic and chemically mediated histamine release. Al- though immunologic release is far less common than chemically mediated release by atracurium (21), it has been reported. Whether cisatracurium, as an atra- curium isomer, has the potential for immunologic re- lease is unknown, and we therefore measured the tryptase activity.

We have previously established that vecuronium, even in large doses, does not cause histamine release. We and others (11,22) have demonstrated that hemo- dynamically vecuronium is among the most safe of muscle relaxants, even when given in large doses by bolus administration. Our current study demonstrates that cisatracurium at equipotent doses or even at 5 X

ED,, confers the same hemodynamic stability and lack of histamine release as does vecuronium. There are, however, important differences. in metabolism, i.e., vecuronium is metabolized to an active metabolite that is subsequently renally excreted (23), whereas

4. Savarese JJ, Viby-Mogensen J, Reich D, Van Aken H. The hae- modynamic profile of cisatracurium. Curr Opin Anaesth 1996; 9(1 Suppl):S34-9.

5. Levy JH, Brister NW, Shearin A, et al. Wheal and flare responses to opioid in humans. Anesthesiology 1989;70:756-60.

6. Doenicke A, Moss J, Lorenz W, et al. Are hypotension and rash after atracurium really caused by histamine release? Anesth Analg 1994;78:967-72.

7. Laroche D, Vergnaud MC, Sillard 8, et al. Biochemical markers of anaphylactoid reactions to drugs. Anesthesiology 1991;75: 945-9.

8. McBride I’, Bradley D, Kaliner M. Evaluation of a radioimmu- noassay for histamine measurement in biological fluids. J Al- lergy Clin Immunol 1988;82:638-46.

9. Moss J. The impact of histamine research on clinical anesthesia and surgery. Agents Actions 1992;C135-48.

10. Enander I, Matsson I’, Nystrand J, et al. A new radioimmuno- assay for human mast cell tryptase using monoclonal antibod- ies. J Immunol Methods 1991;138:39-46.

11. Cannon JE, Fahey MR, Moss J, Miller RD. Vecuronium: the effect of large intravenous doses on plasma histamine. Can J Anaesth 1988;35:350-3.

12. Doenicke A, Moss J, Lorenz W, Hoemecke R. Morphine IV and nalbuphine IV cause histamine and catecholamine increase without relevant hemodynamic changes. Clin Pharmacol Ther 1995;58:81-9.

13. Ostwald I’, Doenicke A, Moss J. New aspects in perioperative histamine release in anesthesia. Curr Opin Anaesth 1995;8: 489-94.

14. Stellato C, de Paulis A, Cirillo R, et al. Heterogeneity of human mast cells and basophils in response to muscle relaxants. Anes- thesiology 1991;74:iO78-86. -

15. Marone G, Stellato C, Mastronardi I’, Mazzarella B. Mechanisms of activation of human mast cells and basophils by general anesthetic drugs. Ann Fr Anesth Reanim 1993;12:116-25.

628 DOENICKE ET AL CISATRACURIUM AND HISTAMINE RELEASE

16. Stellato C, Casalaro V, Ciccarelli A, et al. General anaesthetics induce only histamine release selectively from human mast cells. Br J Anaesth 1991;67:751-8.

17. Stellato C, Cirillo R, de Paulis A, et al. Human basophil/mast cell releasability. Anesthesiology 1992;77:932-40.

18. Hermens JM, Ebertz JM, Hannifin JM, Hirshman CA. Compar- ison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985;62: 124-9.

19. Lawrence ID, Warmer JA, Cohan VL, et al. Purification and characterization of human skin mast cells. J Immunol 1987;139: 3062-9.

20. Laroche D, Lefrancois C, Gerard JL, et al. Early diagnosis of anaphylactic reactions to neuromuscular blocking drugs. Br J Anaesth 1992;69:611-4.

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21. Kumar AA, Thys J, Van Aken HK, et al. Severe anaphylactic shock after atracurium. Anesth Analg 1993;76:423-5.

22. Morris RB, Cahalan MK, Miller RD, et al. The cardiovascular effects of vecuronium (ORG NC45) and pancuronium in pa- tients undergoing coronary artery bypass grafting. Anesthesiol- ogy 1983;58:438-40.

23. Cooper RA, Maddineni VR, Mirakhur RK, et al. Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (ORG 9426) during isoflurane anaesthesia in patients with and without renal failure. Br J Anaestb 1993;71:222-6.