LABORATORY INVESTIGATION epinephrine

Stability of Epinephrine in Alkalinized Solutions Study objective: Increasing the pH of an epinephrine solution favors its oxidation and m a y result in a decrease in its biological activity It is therefore generally assumed that epinephrine and sodium bicarbonate should not be infused in the same IV line during CPR. The aim of this study was to determine the validity of this widely accepted proposition. Design and setting: Two different commercial solutions of epinephrine differing only in the concentration of sodium metabisulfite (0.46% and 0.02%) were studied. Two dosages of each solution type (1 rag~1 m L and 10 mg/lO mL) were diluted in 250 mL of 8.4% sodium bicarbonate. Measurements and main results: The concentration of epinephrine was measured at different times for two weeks. It was found that the concentration of epinephrine decreased slowly to zero after two weeks, and was approximately at 70% and 100% of control values at 30 minutes after alkalinization. Conclusion: It was concluded that epinephrine in an alkaline solution is effectively oxidized but has a slow reaction that m a y not be clinically relevant over short periods of time. [Bonhomme L, Benhamou D, Comoy E, Preaux N: Stability of epinephrine in alkalinized solutions. Ann Emerg Med November 1990;19:1242-1244.]

INTRODUCTION

Laurence Bonhomme* Dan Benhamou, MDt Clamart, France Etienne Comoy, PhD¢ Villejuif, France Nicole Preaux, PhD* Clamart, France From the Laboratoire de Pharmacie et de Toxicologie* and the Departement d~,nesth6sie,t H6pital Antoine B6clere, Clamart, France; and the Laboratoire de Biologie Clinique, Institut Gustave Roussy, Villejuif, France.¢ Received for publication March 1, 1990. Accepted for publication May 31, 1990. Address for reprints: Dan Benhamou, Departement d~,nesth6sie, H6pital Antoine B6clere, 157, rue de la Porte de Trivaux 92141, Clamart, France.

It is generally assumed that epinephrine and sodium bicarbonate should not be infused in the same IV line during CPR. 1 This statement is based on a cheraical interaction with bicarbonate that results in oxidation of epinephrine and then in a decrease of its biological activity.Z,3 However, this assumption might have only theoretical relevance because there has been no clinical report of an adverse outcome related to the simultaneous infusion of both drugs through the same IV line, and we previously reported that after alkalinization of local anesthetic solutions containing epinephrine (alkalinization is to shorten the time to onset and increase the duration of the sensory block during regional anesthesia4,S), the concentration of epinephrine remains unchanged for 24 hours. 6 The purpose of this study was to determine if increasing the pH of epinephrine solutions produces degradation of the molecule.

METHODS Study Solutions Two c o m m e r c i a l solutions of epinephrine-containing sodium metabisulfite (SMB) were compared. Solution 1 (from Laboratoire Aguettant, Lyon, France) contained 1 rag/1 mL epinephrine, 0.46% SMB, and 8.0 mg/ mL sodium chloride (pH 3.0 to 3.5). Solution 2 (from Pharmacie Centrale des H6pitaux, Paris) contained 1 rag/1 mL epinephrine, 0.02% SMB, and 8.7 mg/mL sodium chloride (pH 3.5 to 4.0). Two dosages of each solution (1 and I0 mg/mL) were diluted in 250 mL of molar sodium bicarbonate (8.4%) to obtain two concentrations of epinephrine (1 mg and 10 mg/250 mL). Therefore, the concentrations of epinephrine in these alkaline solutions were 4 ixg/mL and 40 ~xg/mL, respectively. Alkaline solutions remained exposed to ambient air and light. M e a s u r e m e n t s of pH were performed with a p H m e t e r (Radiometer, Copenhagen; prim, 82; sensitivity, 0.01 pH unit) calibrated before each

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EPINEPHRINE B o n h o m m e et al

F I G U R E . C o n c e n t r a t i o n of epinephrine as a function of time after dilution in molar sodium bicarbonate. Closed symbols indicate solutions with a l o w sodium bisulfite concentration; opel~ symbols indicate solutions with a high sodium bJsulfite concentration.*P < .05 versus control period, fP < .05 solution 1 versus solution 2.

Ii

120

Solution 1, epinephrine 1 mg Solution 1, epinephrine 10 mg

[]

Solution 2, epinephrine 1 mg

0

Solution 2, epinephrine 1 mg

100 O

~=~ 80 measurement with known solutions o f p H 4 ,%nd 7. Adrenaline c o n c e n t r a t i o n s were measured by a high-performance liquid c h r o m a t o g r a p h i c (HPLC) procedure with electrochemical detection. After extraction of epinephrine by absorption on alumina after addition of a TRIS buffer, an acetic phase was used for elution. The diluted s a m p l e s were a n a l y z e d w i t h an HPLC system using a CLIN-REP column: The mobile phase contained sodium acetate (50 raM), citric acid (20 mM), octane sulfonate (3.75 mM), dibutylamine (1 mM), and sodium EDTA (0.135 alkalinization of epinephrine raM) for 1 L H20/methanol (95:5 vol/vol). The detection was performed by an amperometric system at 0.70 V (model M 460, Waters, Saint-Quentin en Yvelines, Frances). The sensitivity of the method allows 150 fmo] epinephrine to be detected in the sample volume (50 FL), and the reproducibility for epinephrine is 6.5% (N = 12). Adrenaline c o n c e n t r a t i o n s were measured in solutions of molar sodium bicarbonate (250 mL) before and 30 minutes, 12 hours, and 17 days after alkalinization. Values obtained for epinephrine concentrations were analyzed statistically using one-way analysis of variance followed by Student's t test when necessary. P < .05 was considered statistically significant. RESULTS

The pH of the solutions of epinephrine before alkalinization as well as the changes of pH after dilution of epinephrine in molar sodium bicarbonate are given (Table). Variat i o n s of c o n c e n t r a t i o n s of epinephrine during the study period after dilution of epinephrine in molar sodium bicarbonate are also given (Figure). Oxidation of epinephrine (resulting in a decrease in epinephrine concen32/1243

g ~ 6o o~ ~0 ._.0 ~ 4o c Q_

m

20

Baseline

30 Minutes

12 Hours

17 Days

Time After Alkalinization

TABLE. pH of solutions of epinephrine determined before and after dilution in 250 mL of 8.4% sodium bicarbonate Commercial Solutions

Alkalinized Solutions

1 mg

2.98 + 0.01

7.55 ± 0.02

10 m g

2.98 _ 0.01

7.55 +_ 0.01

Solution 1

Solution 2 1 mg

3.49 + 0.02

7.56 ± 0.02

10 m g

3.49 ± 0.02

7.55 ± 0.02

pH of solutions of molar sodium bicarbonate was 7.55. Solutions 1 and 2 were commercial solutions of epinephrine that differed in concentration of sodium metabisulfite (0.46% and 0.02%, respectively). Values are given as mean _+ SD.

tration and a brownish coloration of the bottle) was less important in the solutions containing the lowest concentration of SMB (solution 2). This was true not only for the very dilute solutions (concentrations expressed as percent of control values, solution h 73.6 ± 1.3, 49.5 ± 2.0 and solution 2:103.0 -_ 3.0, 72.6 ± 1.5 at 30 minutes, 12 hours and 17 days, respectively) but also for the more concentrated solutions (solution 1:68.0 ± 1.6, 58.0 -+ 2.0 and solution 2: 92.0 + 3.0, 78.0 ± 2.0 at 30 minutes and 12 hours, respectively). However, 17 days after a l k a l i n i z a t i o n , epinephrine could not be detected in either solution. Annals of Emergency Medicine

DISCUSSION The epinephrine concentration decreased slowly to zero during two weeks in molar solutions of sodium bicarbonate. This observation is in agreement with the classic description of epinephrine oxidation in adr e n o c h r o m e in a high pH milieu, w h i c h justified, for example, that epinephrine should be infused in a venous line different from that used for b i c a r b o n a t e i n f u s i o n d u r i n g CPR. 1 However, we found that 30 minutes after the addition of epb nephrine (doses in the range of those used during CPR) in a bicarbonate solution, its concentration was still approximately 70% and 100% of con19:11 November 1990

trol values for solutions 1 and 2, respectively. These results confirm the recently d e m o n s t r a t e d p e r s i s t e n c e of epinephrine biological activity i n alkaline solution for at least two hours. 7 The decrease, however, was faster i n solution 1 (ie, solution c o n t a i n i n g the antioxidant agent at the highest concentration - 0.46%). This is i n agreement w i t h previous studies 8 showing that at pH of more than 4, epinephrine is lost more rapidly in the presence of SMB t h a n in its absence; SMB acts as a reducing agent because it is more readily oxid i z e d t h a n e p i n e p h r i n e . 2 I n epinephrine solutions, SMB is the antioxidant of choice because it is more efficient i n acidic s o l u t i o n s . W h e n this antioxidant is placed in a solution at pH of more than 4, it combines w i t h epinephrine to form sulfonic acid derivatives of little or no activity. 9 This m a y have appeared i n

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a l k a l i n i z e d s o l u t i o n s of e p i n e p h r i n e and might have been more i m p o r t a n t i n solutions in w h i c h the concentration of SMB was 25-fold greater (solution 1) t h a n i n the other (solution 2). CONCLUSION Epinephrine in alkaline solutions is effectively oxidized b u t has a slow r e a c t i o n that m a y n o t be c l i n i c a l l y relevant over short periods. It m a y no longer be necessary to separate epinephrine and bicarbonate injections during CPR. The authors thank A Hamon, professor of analytical chemistry, for his advice, Miss A Gire for her technical assistance, and A Vanoutryve for typing the manuscript.

REFERENCES

1. Standards and guidelines for cardiopulmonary resuscitation (CPR)and emergencycardiac care (ECC). JAMA 1986;255:2937-2943. 2. Reynolds JEF: Martindale: The Extra Phar-

Annals of Emergency Medicine

macopeia. London, The Pharmaceutical Press,

1982, p 1291-1292. 3. Newton DW, Fung EII, WilliamsDA: Stability of five catecholamines and terbutaline sulfate in 5% dextrose injections in the absence and presence of aminophylline. A m J Hosp Pharm 1981;38:1314-1319. 4. Di Fazio CA, Carron H, GrosslightKR, et ah Comparison of pH-adjusted lidocaine solutions for epidural anesthesia• Anesth Analg 1986; 65:760-764. 5. Hilgier M: Alkalinizationof bupivacainefor brachial plexus block. Reg Anesth 1985;10: 59-61. 6. BonhommeL, Postaire E, Touratier S, et ah Chemical stability of lidocaineand epinephrine in pH-adjusted parenteral solutions. J Clin Pharm Therap 1988;13:257-261. 7. Parnass SM, BaughmanVL, Milwitch DJ, et al: The effects of pH on the oxidation rate of adrenaline (abstract). Anesthesiology 1987;67 (suppl 3A):A280. 8. Szulczewski DH, Wen-Hai Hong: Adrenaline: Analytical Profiles of Drug Substances.

London, AcademicPress, vol 7, 1978, p 193-229. 9. CartwrightPD: The manufactureand storage of local anesthetics. Reg Anesth 1988~13:1-12.

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Stability of epinephrine in alkalinized solutions.

Increasing the pH of an epinephrine solution favors its oxidation and may result in a decrease in its biological activity. It is therefore generally a...
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