Histamine release after injection of benzodiazepines and of etomidate. A problem associated with the solvent propylene glycol

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© Masson, Paris. A N A P H Y L A C T O I D R I S K

Ann Fr Anesth Reanim, 12: 166-168, 1993 I N A N A E S T H E S I A

Histamine release after injection of benzodiazepines and of etomidate. A problem associated with the

solvent propylene glycol

Liberation d'histamine apres injection de benzodiazepines et d'etomidate.

R61e du solvant propyl6ne-glycol

A. DOENICKE *, W. LORENZ**, R. HOERNECKE *, A.E. NEBAUER *, M. MAYER *

• Institut for Anaesthesiologie der LMU MOnchen, Innenstadtkliniken, PettenkoferstraBe 8a, 8000 MOnchen 2, Germany

• * Theoretische Chirurgie, Philipps-Universitgt, Marburg, Germany

RI~SUM#: Beaucoup de m6dicaments, surtout quand ils sont inject6s rapidement, peuvent induire une lib6ration d'histamine. Une 6tude en ,, cross-over ~ et simple aveugle a 6t6 r6alis6e chez dix volontaires sains. Ils ont 6t6 pr6m6diqu6s avec respectivement 10 mg - 70 kg t de diaz6pam i.v. et 1 mg - 70 kg ~ de lorm6taz6pam i.v., 30 min avant une injection intraveineuse de 0,15 mg- kg ~ d'6tomidate. Le lorm6ta- z6pam et l'6tomidate ont produit des augmentations distinctes du niveau d'histamine plasmatique chez deux sujets. Les pics maximaux d'histamine aprc3s lorm6taz6pam ont 6t6 respectivement de 2,05 et 2,7 ng- ml J e t , apr~s 6tomidate, de 1,85 et 3,2 n g - ml -~. Les deux m6dicaments sont solubilis6s dans lc propyl~ne-glycol, solvant qui confute une tr~s haute osmolalit6 (6 750 mosm - kg ~ pour le lorm6taz6pam, 4 900 m o s m . kg i pour F6tomidate). Des signes cliniques comme une tachycardie, une hypotension art6rielle ou des r6actions allergiques n'ont 6t6 not6s dans aucun cas. Cette lib6ration limit6e d'histamine semble cons6cutive au dommage tissulaire et 6rythrocytaire 1i6 ~ I'hyperosmolarit6.

D u r i n g i n d u c t i o n a n d m a i n t e n a n c e o f a n a e s t h e - sia a v a r i e t y o f p o t e n t d r u g s a r e a d m i n i s t e r e d v e r y o f t e n i n r a p i d s e q u e n c e . E a c h o f t h e d r u g s u s e d c a n p o t e n t i a l l y c a u s e h i s t a m i n e r e l e a s e . I n t h e l a s t t w o d e c a d e s m a n y p h a r m a c o l o g i s t s a n d a n a e s t h e - s i o l o g i s t s h a v e i n v e s t i g a t e d n u m e r o u s h y p n o t i c s , n a r c o t i c s a n d m u s c l e r e l a x a n t s in t h i s r e s p e c t [1, 11, 13]. A m o n g t h e b e n z o d i a z e p i n e s i n v e s t i g a t e d s o f a r , o n l y f l u n i t r a z e p a m h a s b e e n s h o w n t o r e l e a s e h i s t a m i n e [1].

O r a l p r e m e d i c a t i o n w i t h b e n z o d i a z e p i n e s , u s u a l l y 1 h o u r b e f o r e t h e o p e r a t i o n , i n c r e a s i n g l y is r e p l a c e d b y t h e i . v . a d m i n i s t r a t i o n o f p a r e n t e r a l f o r m u l a t i o n s o f t h e s e d r u g s 10-20 m i n u t e s p r i o r t o i n d u c t i o n o f a n a e s t h e s i a . I n t r a v e n o u s p r e m e d i c a - t i o n w i t h b e n z o d i a z e p i n e s h a s p r o v e n t o e f f e c t i v e l y r e d u c e t h e m y o c l o n i c m o v e m e n t s a s s o c i a t e d w i t h t h e u s e o f e t o m i d a t e [2]. T h e a i m o f t h i s t r i a l is t o i n v e s t i g a t e w h e t h e r i.v. a d m i n i s t r a t i o n o f t h e t w o b e n z o d i a z e p i n e s d i a z e p a m a n d l o r m e t a z e p a m , u s e d in c o m b i n a t i o n w i t h e t o m i d a t e , c a u s e s h i s t a m i n e r e l e a s e .

PATIENTS AND METHODS

After approval by the institutional ethics committee and after having obtained their informed consent, 10 healthy volunteers (age 20-30 years, weight 50-90 kg) were investigated in this single-blind, crossover study. The investigators were not blin- ded because, due to its solubility characteristics, it is not possible to dilute diazepam to a volume of 5 ml, as needed for the administration of lormetazepam. The subjects had a four day recovery interval after the first anaesthesia with etomidate and premedication with one of the two benzodiazepines. The sequence of injection of diazepam and lormetazepam in every volunteer was randomized.

Following amounts of drugs were injected into a distal forearm vein : diazepam 10 mg - 70 kg ~ or lormetazepam 1 r a g - 7 0 kg -t, 30 rain prior to etomidate 0.15 m g . kg ~. The time table of trial procedure is schematically presented in figure 1.

Blood samples were drawn through a cannula placed in an antecubital vein and plasma histamine levels were measured according to the fluorometric method described by LORENZ et al. [10]. Responders were subjects which presented at least a 40 % increase in plasma histamine levels from the previous baseline value.

Heart rate was continuously monitored and blood pressure was measured in two rain intervals.

Presented at the meeting ,, New Trends in Anaphylactoid Risk in Anaesthesia ~,. Nancy (France), 11-12 June 1992.

Tires ~ part : A. Doenicke.

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HISTAMINE RELEASE AFTER L O R M E T A Z E P A M A N D ETOMIDATE 167

RESULTS

D i a z e p a m solved in benzyl-alcohol did not release substantial amounts of histamine (slight mean increase from 0.35 to 0.61 ng - ml l).

Plasma levels were well below 1 n g - m l -~ M e a n plasma histamine values _+ SD are presented in table I.

Table I. - - Plasma histamine levels (ng • ml 1) after administration of d i a z e p a m 10 m g . 70 kg 1 i.v. and Iormetaze.pam 1 mg • 70 kg -1 i.v., 30 min before e t o m i d a t e 0.15 mg • k g - ' i . v .

Before After Before After

Diazepam Etomidate

0.35 (0.16) 0.61 (0.17) 0.41 (0.12) 0.54 (0.22)

Lormetazepam Etomidate

046 (0.22) 0.98 (0.82) 0.53 (0.33) 0.94 (0.95)

Mean -+ SD ; n = 10 volunteers ; crossover study with two different i.v.

premedications ( d i a z e p a m and I o r m e t a z e p a m , respectively) 30 min before ctomidate injection ; 4 day interval between study sessions.

L o r m e t a z e p a m solved in propylene glycol showed a distinct histamine release in two subjects (fig. 1). According to the elimination kinetics of histamine the levels returned to baseline values within ten minutes. The subsequent injection of etomidate solved in propylene glycol (30 minutes later) caused a further liberation of histamine.

Both volunteers did not show any cardiovascular reactions expected with these histamine concentrations. In both instances diazepam was given on the

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Fig. 1. - - Histamine plasma levels in two volunteers after injection of diazepam, lormetazepam (6,750 mosm - kg J) and etomidate (4,900 mosm - kg-I).

Histamine plasma levels (ng - ml t) measured in blood samples drawn before and 5 min and l0 min after diazepam/lormetaze- pare i.v. premedication and I rain after etomidate injection.

Etomidate was injected 30 min after benzodiazepine administration. There was a four day interval between the two induc- tion procedures.

first trial day and l o r m e t a z e p a m on the second day, i.e. four days later. Histamine levels in a third volunteer rose from 0.75 to 1.15 n g . ml -j, but did not present a true histamine release according to our definition.

Myocloni after e t o m i d a t e application were not observed after premedication with l o r m e t a z e p a m , but was seen in a mild form in one subject after diazepam.

DISCUSSION

A previous study on 10 volunteers revealed m o d e r a t e histamine release after i.v. administration of flunitrazepam in 5 subjects with a maximal histamine level of 1 n g - ml -l. These were associated with cutaneous s y m p t o m s indicating local histamine liberation [5]. Flunitrazepam was solved in 829 m g . ml -~ p r o p y l e n e glycol. In 1978, we found elevated histamine levels associated with clinical symptoms ( e r y t h e m a ) in volunteers receiving the muscle relaxants alloferin, p a n c u r o n i u m or suxa- m e t h o n i u m in combination with etomidate [4]. A t that time we would not find an explanation for histamine release after flunitrazepam or e t o m i d a t e i n combination with muscle relaxants.

In 1973, we had shown that etomidate did not release histamine [3]. WAXK1NS (personal c o m m u - nication) suggested the possibility of histamine release after etomidate, in such small amounts, however, that due to its fast elimination f r o m the circulation it could not cause h a e m o d y n a m i c effects. This was based on the observation of subclinical reactions like c h e m o t a x i s of leukocytes through the surrounding tissue. The production of anaphylatoxins following C3-activation reached its highest value 30-40 minutes after e t o m i d a t e administration, whereas methohexital showed this effect already after 5 minutes.

O u r own investigations on etomidate solved in various solvents m a y now help to resolve the problem on histamine release after etomidate. In 1973, we had studied histamine release with a formulation of e t o m i d a t e sulphate solved in phos- phate buffer. This e t o m i d a t e p r e p a r a t i o n had a p H of 3.3 and an osmolality of 270 m o s m . kg i [9]

and did not cause histamine release [3]. Since 1977 etomidate is f o r m u l a t e d in 35 vol % p r o p y l e n e glycol_ We now know that its osmolality of 4,900 m o s m - k g -l is conveyed by the content of propylene glycol in the drug p r e p a r a t i o n [6]. It has been shown that r e p l a c e m e n t of propylene glycol with lipid emulsion p r e v e n t e d thrombophlebitis of diazepam [7] and significantly reduced the occu- fence of pain on injection, thrombophlebitis [2]

and haemolysis [12] after e t o m i d a t e injection.

In the present study, the volunteers received etomidate in 35 vol % p r o p y l e n e glycol on two occasions and for premedication, once diazepam in benzylalcohol, and once l o r m e t a z e p a m in 50 vol %

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168 A. DOENICKE et aL

propylene glycol, respectively. Lormetazepam in p r o p y l e n e g l y c o l h a s a n o s m o l a l i t y o f 6,750 mosm • kg-l [6].

We believe that not only the first injection of etomidate after diazepam but also the injection of lormetazepam and etomidate four days later, may cause osmotical tissue damage. The unphysiologic osmolality of these drugs therefore can cause histamine release from damaged endothelium a n d / o r mast cells. The occurrence of pain and thrombophlebitis reported in previous studies [2, 14] can be interpreted as symptoms of irritation of the vascular tissue.

Interestingly the high histamine levels after lormetazepam (2.05 and 2_7 n g - ml -j) and etomidate (1.85 and 3.2 n g - m l -I) observed in two volunteers were not associated with haemodynamic reactions or other side effects seen with similar histamine concentrations. This may be explained by the very short presence of histamine in the circulation suggested by WATKINS and the limited histamine release from destroyed blood and tissue cells, not sustained by cascade mechanism of me- diators [13].

Independently from this, we advocate the repla- cement of solvents that convey an unphysiologic osmolality to commercial drug preparations and therefore cause vascular and cellular sequelae. Stu- dies comparing etomidate solved in propylene glycol and etomidate solved in lipid emulsion with medium chain triglycerides have clearly demonstra- ted the advantages - - no pain on injection, no thrombophlebitis, no haemolysis - - of the prepara- tion containing the lipid solvent at a physiologic osmolality (400 mosm - kg -t ; pH = 7.6 [6]) [2].

Since February 1992, etomidate is available in Germany in a medium chain triglycerides containing lipid emulsion (Etomidat-Lipuro ®). A new solvent should also be found for other drugs, especially benzodiazepines like lormetazepam, lorazepam or flunitrazepam, yet solved in propylene glycol.

Promising results have been presented by HABA- ZEaL et al. in animal studies with propanidid formulated in liposomes. They reported a dramatic reduction of mortality due to anaphylactic reactions in rats from 86 % with propanidid solved in cremophor vs 0 % propanidid in the liposome formulation [8].

REFERENCES

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2. DOENICKE A, KUGLER A, VOLLMANN N, SUTrMANN H, TAEGER K. Etomidat mit einem n e u e n LOsungsvermittler.

Klinisch-experimentelle U n t e r s u c h u n g e n zur Venenvertr~ig- lichkeit und Bioverf0_gbarkeit. Anaesthesist, 3 9 : 475-480,

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5. DOENICKE A , LORENZ W. Histaminliberierung dutch Fluni- trazepam (pp 62-66). I n : Klinische Anaesthesiologie u n d Intensivtherapie, vol. 17 : R o h y p n o l (Flunitrazepam).

AHNEFELD F W et al. eds. Springer, Berlin, 1978.

6. DOENICKE A, NEBAUER A E , HOERNECKE R, MAYER M, ROIZEN MF. Osmolalities of propylene glycol-containing drug formulations for parenteral use. Should propylene glycol be used as a solvent ? Anesth Analg, 7 5 : 431-435, 1992.

7. GRAHAM CW, PAGANO R R , KATZ RL. Thrombophlebitis after intravenous diazepam. Can it be prevented ? Anesth Analg, 5 6 : 409-413, 1977.

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NEBAUER A E , DOENICKE A, HOERNECKE R, ANGSTER R, MAYER M. D o e s etomidate cause haemolysis ? Br J Anaesth, 6 9 : 58-60, 1992.

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11.

12.

13.

14.

ABSTRACT: Many drugs, especially w h e n given in rapid sequence can cause histamine release. T e n healthy volunteers were premedicated with diazepam 10 mg . 70 kg ~ i.v. and l o r m e t a z e p a m 1 m g . 70 kg ~ i.v., respectively, 30 rain prior to etomidate 0.15 m g - kg i i.v. in a single-blind, crossover study. T h e benzodiazepine Iormetazepam and the hypnotic etomidate caused distinct increases in histamine plasma levels in two subjects. Maximal histamine levels after Iormetazepam were 2.05 and 2.7 ng . ml ~, and after etomidate 1.85 and 3.2 n g - ml ~, respectively. Both drugs are solved in propylene glycol, a solvent that conveys very high osmolality ( l o r m e t a z e p a m 6 750 m o s m . kg J, e t o m i d a t e 4 900 m o s m kg t). Clinical s y m p t o m s , like tachycardia, hypotension or allergic reactions, associated with similar histamine levels were not seen in either case. This limited histamine release appears to be caused by osmotic damage of tissue and blood cells.