Comparison of intraosseous and intravenous routes of anticonvulsant administration in a porcine model

ORIGINAL CONTRIBUTION anticonvulsant medication, administration; phenobarbital, intraosseous; phenytoin, intraosseous

C o m p a r i s o n of Intraosseous and Intravenous Routes of A n t i c o n v u l s a n t Administration in a Porcine Model During status epilepticus, rapid IV access for the administration of anticonvulsant drugs can be a very difficult and time-consuming procedure. Our study evaluated whether therapeutic serum levels of phenobarbital and phenytoin could be obtained by the intraosseous route. Twenty domestic swine weighing 10 to 20 kg were divided into two groups (ten each). In one group, phenobarbital 20 mg/kg was administered either intraverlously (five) or intraosseously (five). The second group received phenytoin 15 mg/kg either intravenously (five) or intraosseously (five). All animals had samples for anticonvulsant levels drawn from an indwelling arterial cannula at one, three, five, seven, ten, 15, and 30 minutes after dosing. Anticonvulsant levels were found to be statistically significantly higher with IV administration (P < .01). However, phenobarbital levels were therapeutic by the intraosseous route, while phenytoin levels were below the therapeutic range after the ten-minute interval. Bone marrow levels 45 minutes after infusion were 13.5 ~g/mL (phenobarbital) and 11.5 ~g/mL (phenytoin). Our study demonstrates that current IV dosing of phenobarbital 20 mg/kg given intraosseously obtains and maintains therapeutic serum levels. Phenytoin 15 mg/kg does not maintain therapeutic levels and cannot be recommended for intraosseous administration. [Jaimovich DG, Shabino CL, Ringer TV, Peters GR: Comparison of intraosseous and intravenous routes of anticonvulsant administration in a pordne model. Ann Emerg Med August 1989;18:842-846.]

David G Jaimovich, MD Charles L Shabino, MD Thomas V Ringer, MD Gary R Peters, MD Kalamazoo, Michigan

INTRODUCTION

Address for reprints: David G Jaimovich, MD, Bronson Methodist Hospital, Pediatric Intensive Care Service, 252 East Lovell Street, Kalamazoo, Michigan 49007.

Rapid IV access for the administration of anticonvulsant drugs in the seizing infant can be one of the most difficult and time-consuming procedures that a physician frequently faces. An alternate way to administer medications, recently reintroduced, is the intraosseous route.1 Many drugs (eg, atropine, bicarbonate, epinephrine, diazepam) frequently administered by the intraosseous route in life-threatening emergency situations have been studied. 2-4 To prevent seizure activity, one must deliver both short- and long-acting anticonvulsants to avoid recurrence of the seizures.5, 6 This not only aids in the ablation of the seizure activity but also promotes the prevention of brain damage from the hypoxia of prolonged ictal activity. 4 Our study was conducted to evaluate whether therapeutic serum levels of phenobarbital and phenytoin can be obtained by the intraosseous route.

From the Pediatric Intensive Care Service and the Department of Pediatrics, Bronson Methodist Hospital, Michigan State University School of Medicine, Kalamazoo. Received for publication December 27, 1988. Revision received March 27, 1989. Accepted for publication April 4, 1989. Presented at the American Academy of Pediatrics Annual Meeting, Critical Care Section, San Francisco, California, October, 1988. Funding provided by the Bronson Clinical investigation Unit Community Research Fund.

MATERIALS A N D METHODS Twenty domestic swine weighing 10 to 20 kg were anesthetized with ketamine 20 mg/kg IM. The animals then were given inhalation anesthesia with halothane. Subsequently, the trachea was intubated with a no. 5 or no. 6 endotracheal tube and ventilation was controlled. The animals were ventilated on 0.5 oxygen concentration (FIO2}. A lead II ECG was recorded throughout the experiment to monitor heart rate and rhythm. The left femoral artery was cannulated with a 20-gauge catheter for continuous blood pressure monitoring and blood sampling. A 20-gauge catheter was inserted into a dorsal vein of the distal right forelimb in all animals for administration of subsequent medications when indicated. IV fluids were administered as 5% dextrose in water at a rate of 4 mL/kg/hr, and tempera-

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ANTICONVULSANT ADMINISTRATION Jaimovich et al

FIGURE 1. I n t r a o s s e o u s v e r s u s i n t r a venous dosing -

phenobarbital.

60

FIGURE 2. I n t r a o s s e o u s v e r s u s i n t r a venous dosing -

phenytoin.

ture was maintained between 37 and 38 C. Before administration of anticonvulsant medication, the animals were assigned to one of four groups: IV phenobarbital, intraosseous phenobarbital, IV p h e n y t o i n , or intraosseous phenytoin. After skin preparation, a 16-gauge adjustable length aspiration needle (Monoject Illinois Sternal-Iliac, Sherwood Medical, St Louis) was inserted into the broad, flat anteromedial surface of the tibia 1 cm below the tibial tuberosity in those animals receiving intraosseous medications. It was inserted e i t h e r p e r p e n d i c u l a r to the bone or in a slightly caudal direction to prevent injection of fluid or drugs into the epiphysial plate. Once the needle was advanced into the marrow, the obturator was removed and the position of the needle was confirmed by free aspiration of blood and m a r r o w c o n t e n t s s u c h as fat and bone spicules. All groups of animals received a 10-mL saline flush to clear the cannulas. The first group (five) was administered phenobarbital 20 m g / k g through a peripheral IV line. The second group (five) was a d m i n i s t e r e d phenobarbital 20 mg/kg through the intraosseous route. The third group (five) was administered phenytoin 15 m g / k g through a peripheral IV line. The remaining group (five) received phenytoin 15 mg/kg through the intraosseous route. Phenobarbital was a d m i n i s t e r e d over one m i n u t e and phenytoin over two. Serum phenytoin and phenobarbital samples were drawn from the arterial line at one, three, five, seven, ten, 15, and 30 minutes after the adm i n i s t r a t i o n of the a n t i c o n v u l s a n t drug by both the IV and intraosseous r o u t e s . All a n t i c o n v u l s a n t b l o o d levels were assayed w i t h a fluorescence polarization i m m u n o a s s a y on an Abbott TDx system (Abbott Laboratories, N o r t h Chicago, Illinois). Reagents were purchased from Abbott and used according to manufacturer's specifications. Both assays had b e t w e e n - r u n coefficients of a variance of 3.0% t h r o u g h o u t the linear range. R e p r o d u c i b i l i t y in the same 88/843

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run was 1.5%. Two additional animals were studied for intraosseous a n t i c o n v u l s a n t levels. The tibia of the animal receiving intraosseous phenobarbital was removed at the conclusion of the exAnnals of Emergency Medicine

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periment with the intraosseous needle in place and was preserved in formalin. T h e contralateral tibia was also removed at the conclusion of the experiment as a control and was preserved in the s a m e m a n n e r . Sire18:8 August 1989

~ - Injection

site

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ilarly, the tibias of one of the animals receiving i n t r a o s s e o u s p h e n y t o i n were removed and preserved in the same manner. The phenytoin specimen was examined by a veterinary pathologist for evidence of damage to the cells or supporting structures of the injected tibia. Samples from the control tibias and the tibias that had phenobarbital and phenytoin infusions were frozen in liquid nitrogen, crushed, and then h o m o g e n i z e d w i t h 70 mL 1 M KH2PO 4 (pH 2.7) for approximately five minutes. The homogenates were centrifuged at 4,000g for 30 minutes. 7 The resulting supernatants were subiriitted for assay using a fluorescence polarization immunoassay, and the phenobarbital and phenytoin concentrations were determined as described previously. Statistical analysis compared the means of the drug levels at each time point between the two routes of administration. This was performed by 18:8 August 1989

i

a two-tailed Student's t test. P < .05 was considered statistically significant. The animals were housed individually in the animal care facility of the Upjohn Research Facility in accordance with their institutional animal care guidelines. RESULTS

By one-way analysis of variance, there were no significant differences in blood pressure (dr, 3, 16; F, .30; P > .83) or heart rate (dr, 3, 19; F, .74; P > .54) b e t w e e n a n y in the four groups. Baseline systolic blood pressure and heart rate (mean ± SD) values for the four groups were IV phenobarbital (110 + 7 m m Hg and 159 ± 20 beats/min), intraosseous phenobarbital (109 ± 10 m m Hg and 149 ± 12 beats/rain), IV phenytoin (104 ± 2 m m Hg and 167 _+ 10 beats/ min), and intraosseous p h e n y t o i n (107 ± 5 m m Hg and 154 ± 17 beats/ rain). Annals of Emergency Medicine

FIGURE 3. (A) Pig tibia treated with intraosseous phenytoin. Note injection site without other gross abnormalities. (B) ControJ (untreated) pig tibia. FIGURE 4. IA) Microscopic section of bone marrow treated w~th IV phenytoin showing lack of mature cellular elements compared with nontreated marrow (B). Serum a n t i c o n v u l s a n t levels in swine receiving phenobarbital 20 mg/kg and intraosseously are shown (Figure 1). Serum phenytoin levels in animals receiving 15 mg/kg IV and intraosseously are also shown (Figure 2}. For each of the anticonvulsants, the m a x i m u m c o n c e n t r a t i o n occurred at one minute after infusion b o t h i n t r a v e n o u s l y and i n t r a o s seously. Therapeutic phenobarbital levels (15 to 40 ~tg/mLI were attained throughout the study period by both routes of administration. Phenytoin 844/89

ANTICONVULSANT ADMINISTRATION Jaimovich et al

dosed i n t r a v e n o u s l y resulted in therapeutic drug concentrations (10 to 20 ~g/mL) at each t i m e point; however, by i n t r a o s s e o u s d o s i n g , t h e d r u g l e v e l s w e r e s u b t h e r a p e u t i c at t h e ten-, 15-, and 3 0 - m i n u t e s a m p l i n g times. A t each t i m e p o i n t for b o t h anticonvulsants, the 1V route of administration yielded a significantly higher (P < .01) drug c o n c e n t r a t i o n than did the intraosseous route. The area under the curve 0 to 30 m i n u t e s ( m e a n + SD) for IV phenobarbital was 984 + 71 and for intraosseous phenobarbital was 698 -+ 122. C o m p a r i s o n by t w o - t a i l e d Student's t test showed that the area under the curve for the IV phenobarbital was significantly higher (P = .003). For phenytoin, the area under the c u r v e 0 to 30 m i n u t e s for t h e IV r o u t e (426 ___ 16) w a s s i g n i f i c a n t l y higher (P - .0004) than for the intraosseous route (273 _+ 54). T h e gross and m i c r o s c o p i c b o n e m a r r o w sections are s h o w n (Figures 3 and 4). H i s t o l o g i c e x a m i n a t i o n of the formalin-fixed, decalcified bone m a r r o w at the intraosseous injection site of p h e n y t o i n s h o w e d a l t e r a t i o n in the m a r r o w cellularity. There was a l a c k of m a t u r e c e l l u l a r e l e m e n t s (especially erythrocytes) at the site of injection. The injection procedure " w a s h e d " the m o r e m a t u r e c e l l u l a r e l e m e n t s a w a y from the site; however, t h e r e was no h i s t o l o g i c evidence that this change w o u l d not be reversible. The concentration of the r e m a i n i n g cells was a l o n g t h e trabecular bone, and there was no evidence of crystallization s e e n on the h i s t o p a t h o l o g i c slides. T h e c o n t r o l (contralateral) tibia bone marrow slides were normal. The bone marrow phenobarbital l e v e l at 45 m i n u t e s after i n f u s i o n was 13.5 p~g/mL. T h e bone m a r r o w p h e n y t o i n level at 45 m i n u t e s after infusion was 11.50 ~xg/mL.' DISCUSSION W h e n children and infants present in s t a t u s e p i l e p t i c u s , r a p i d a n t i epileptic therapy is required, If IV access is n o t r e a d i l y a v a i l a b l e , o t h e r routes m u s t be used. Unfortunately, drugs administered by the intram u s c u l a r and rectal routes of admini s t r a t i o n are absorbed erratically. In r e c e n t years, t h e r e has b e e n a resurgence in use of the i n t r a o s s e o u s route as an alternative to venous cann u l a t i o n in the a c u t e l y ill infant or 90/845

child.Z,3 O u r study was conducted to comp a r e t h e i n t r a o s s e o u s w i t h t h e IV route of a d m i n i s t r a t i o n of phenobarbital and p h e n y t o i n by e x a m i n i n g serum phenobarbital and phenytoin levels. D o m e s t i c swine were chosen as the e x p e r i m e n t i n g m o d e l s because of s i m i l a r i t i e s b e t w e e n t h e i r tibias and those of infants. Also, the similarity of their cardiovascular s y s t e m to that of h u m a n beings allowed for m o n i t o r i n g of h e m o d y n a m i c changes while the respective drugs were administered. The weight and developm e n t of the bone m a r r o w of 10- to 14-week-old swine is similar to that of infants or small children. 5 T h e c u r r e n t l y r e c o m m e n d e d IV l o a d i n g doses of p h e n o b a r b i t a l and p h e n y t o i n are 20 and 15 to 18 mg/kg, r e s p e c t i v e l y . In o u r study, t h e authors used the lower dose (15 mg/kg) of p h e n y t o i n to avoid possible cardiov a s c u l a r c o m p r o m i s e . To f a c i l i t a t e flow from the bone to the central circulation, each a d m i n i s t r a t i o n of phenobarbital or p h e n y t o i n was followed by a 10-mL s a l i n e flush. T h i s also was done for the peripheral IV route to m a i n t a i n a consistent experimental design. In o u r s t u d y , t h e d a t a d e m o n s t r a t e d s e r u m b l o o d l e v e l s of phenobarbital and p h e n y t o i n after IV adm i n i s t r a t i o n to be statistically significantly higher than after intraosseous a d m i n i s t r a t i o n at each t i m e p o i n t (P < .01). Phenobarbital levels r e m a i n e d w i t h i n the t h e r a p e u t i c range at 30 m i n u t e s for both the IV route (26.9 _+ 2.3 ~g/mL) and t h e i n t r a o s s e o u s r o u t e (19.5 + 3.2 ~g/mL). O u r data demonstrated that intraosseous phenytoin reached the circulation and achieved a therapeutic level w i t h i n one m i n u t e of administration. It did not, however, r e m a i n w i t h i n the therapeutic range as levels at ten, 15, and 30 m i n u t e s after dosing were below the therapeutic range. Our data revealed that the bone m a r r o w c o n c e n t r a t i o n of p h e n y t o i n was 11.50 ~ g / m L after 45 m i n u t e s . Therefore, this suggests that the p h e n y t o i n had not yet fully distributed from the site of a d m i n i s t r a t i o n to the s y s t e m i c circulation. This is the first drug (phenytoin) shown not to achieve e q u i v a l e n t t h e r a p e u t i c blood levels w h e n similar doses are given by IV and intraosseous routes. This w o u l d therefore suggest that similar pharmacokinetic studies Annals of Emergency Medicine

should be done for all drugs given intraosseously. In contrast to our study, a brief report by B r i c k m a n et al s suggests that phenobarbital levels by the intraosseous route were higher than those achieved by the IV route using similar doses. Their study m e a s u r e d only p h e n o b a r b i t a l levels to t e n m i n u t e s after injection. No comparison s t u d i e s of p h e n y t o i n g i v e n i n t r a venously and intraosseously have been reported. CONCLUSION O u r study data show that by using s t a n d a r d IV l o a d i n g d o s e s of p h e nobarbital, statistically significantly lower, y e t t h e r a p e u t i c l e v e l s w e r e o b t a i n e d by t h e i n t r a o s s e o u s r o u t e w h e n c o m p a r e d w i t h the IV route. On the other hand, w h e n a standard IV loading dose of p h e n y t o i n was adm i n i s t e r e d intraosseously, therapeutic levels were not maintained. Therefore, we r e c o m m e n d the intraosseous r o u t e as an a l t e r n a t i v e for the a d m i n i s t r a t i o n of phenobarbital, a long-acting anticonvulsant, when intravascular access is n o t available. We c a n n o t r e c o m m e n d t h e i n t r a osseous route for p h e n y t o i n because therapeutic levels in our study were n o t maintained. Further studies are needed to evalu a t e t h e p r o l o n g e d a b s o r p t i o n of p h e n y t o i n from the bone marrow. Finally, we suggest that all drugs given by t h e i n t r a o s s e o u s r o u t e s h o u l d h a v e careful e v a l u a t i o n before ass u m i n g that IV doses achieve therapeutic levels when given intraosseously. The authors express their appreciation to the Upjohn Company, Terry Gilbertson, PhD, and Tom Arnold for technical assistance; Richard Stockrnar, PhD, for laboratory assistance; Mark Paulson, PharmD, for pharmacologic support; and Chris I~elthoff for her patient and endless assistance in the preparation of this manuscript.

REFERENCES

1. Rosetti VA, Thompson BM, Miller J, et al: Intraosseous infusion: An alternative route of pediatric intravascular access. Ann Ernerg Med 1985;14:885-888. 2. Berg RA: Emergency infusion of catecholamines into bone marrow. A m J Dis Child 1984;138:810-811. 3. Spivey WH, Lathers CM, Malone DR, et al: Comparison of intraosseous, central, and peripheral routes of sodium bicarbonate administration during CPR in pigs. Ann Emerg Med 18:8 August 1989

1985;14:1135-1140. 4. Shoor PM, BerryhilI RE, Benumof JL: Intraosseous infusion: Pressure-flow relationship and pharmacokinetics. J Trauma 1979;19:772-774.

pentylenetetrazolqnduced epileptogenic activity in pigs. Ann Ernerg Med 1987;17:156-158.

5. Spivey WH, Unger HD, Lathers CM, et al: In-

6. Pearce JL, Sharman JR, Forster RM: Phenobarbital in the acute management of febrile convulsions. Pediatrics 1977;60:569-572.

traosseous

7. Ramsay RE, Hammond EJ, Perchalski RJ, et

diazepam

suppression

of

al: Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 1979;36:535-539.

8. Brickman K, Rega P, Guinness M: Comparative study of intraosseous versus intravenous infusion of phenobarbital. Ann Emerg Med 1986;15:644-645.

Call for Abstracts THIRD INTERNATIONAL CONFERENCE ON EMERGENCY MEDICINE TORONTO, ONTARIO, CANADA JUNE 24-29, 1990 The Third International Conference devoted solely to Emergency Medicine will be held in Toronto, Ontario, Canada, June 24-29, 1990. George Podgomy, MD, Chairman of the Intemational Affairs Task Force, is now accepting abstracts for review for presentation during the Conference. Abstracts should be limited to 200 words and the material should be original, ie, not previously published or presented at a conference elsewhere. The abstract should be typewritten on 81/2"x 11" paper, double spaced. Full names, tides, mailing address, and phone number should be given on a separate sheet. Sessions will be devoted to the presentation of selected scientific papers. These papers may cover a range of significant areas of emergency medicine, from resuscitation and toxicology to radiology and research. Submit the original and four copies of your abstract to: George Podgomy, MD, Chairman, International Affairs Task Force, American College of Emergency Physicians, PO Box 619911, Dallas, Texas 75261-9911. Deadline .for submission of abstracts is August 31, 1989.

Annals of Emergency Medicine, as the official journal of the American College of Emergency Physicians and the Society for Academic Emergency Medicine, shall have the right of first refusal for publication of all papers from the United States submitted to ACEP and selected for presentation. Any requests for further information regarding the United States' participation in this conference should be directed in writing to Dr Podgomy at the above address. 18:8 August 1989

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