Comparison of intraosseous versus intravenous loading of phenytoin in pigs and effect on bone marrow

Original Contributions

Comparison of lntraosseousVersusIntravenous Loadingof Phenytoinin Pigs andEffecton BoneMarrow CPT PAUL J. VINSEL, DO, MC, USA,* CPT GREGORY P. MOORE, MD, MC, USA,t CPT KEVIN C. O’HAIR, DVM, VC, USA* Much recent literature supports the resurgence of the intraosreous mute of access In pediatrics. lntraosseous lines provide a timely noncollapsable mute to the circulation in medical or traumatic emergencies when Intravenous access is not possible. There has been no controlled study comparing intravenous and intraosseous loading of phenytoin. A 15 mg&g dose of phenytoin was administered over 15 minutes to pigs by either the intravenous (n = 6) or tiblal intraosseous mute (n = 6). Femoral artery blood samples were drawn every 5 minutes for 36 minutes after initiation of infuslon to determine phenytoin levels. There was no statistical difference between the two groups using analpls of variance repeated measures (P = .160). Microscopic examination of the cortex and marrow at the intraosseous site in these pigs was normal 5 weeks postlnfuslon. The authors conclude that the intreosseous mute is an et fectiw alternative to intravenous loading of phenytoin without permanent damage to the marrow. (Am J Emerg Mod 1990;6:161-163. 0 1990 by W.6. Saunders Company.)

Intravenous (IV) access in the critically ill pediatric patient is often a difficult procedure even for the well-trained emergency physician. However, access for the administration of fluids and medications is an immediate concern in the resuscitation of the child. Alternatives to peripheral IV access include central venous cannulation, venous cutdown, and endotracheal administration. Central venous cannulation and venous cutdown are both time consuming and frought with complications when the endotracheal route is not available for fluid resuscitation and is limited to atropine, diazepam, nalaxone, lidocaine, and epinephrine administration. Another technique useful when peripheral IV access is From the *Emergency Medicine Residency, Darnall Army Community Hospital, Ft Hood, TX, the tEmergency Medicine Residency, Maricopa Medical Center, Phoenix, AZ, and the $Biological Research Service, Department of Clinical Investigations, William Beaumont Army Medical Center, El Paso, TX. Manuscript received September 19, 1988; revision accepted May 17, 1989. The opinions or assertions presented do not necessarily reflect those of the Department of Defense or the Department of the Army. Presented in part at the Tri-Service Symposium in Emergency Medicine, San Antonio, TX, April 4, 1988. Address reprint requests to CPT Vinsel, MD: Department of Emergency Medicine, Darnall Army Community Hospital, Ft Hood, TX 76644. Key Words: Intraosseus. phenytoin, pediatrics. 0 1990 by W.B. Saunders Company. 0735-6757/90/0803-0001$5.00/0

not available is intraosseous

(IO) infusion. Recent literature has recommended IO use in resuscitation if IV access is not obtained within 5 minutes.’ Tocantins popularized IO infusion in the 194Os.*” This technique was abandoned soon after the advent of peripheral IV catheters. Because of the ease of the procedure, its low complication rate, and its performance speed, the bone marrow can once again be used for the administration of fluids and medication.4 In 1986, Walsh-Kelly et al reported the administration of phenytoin IO with success in a 2-year-old child. Seizure activity was stopped and therapeutic serum levels of phenytoin were attained.5 The purpose of our study is to determine if IO infusion of phenytoin in a pig model will produce serum phenytoin levels comparable to that of IV administration and to determine if any long-term damage to the bone marrow will result. MATERIALS AND METHODS

Our study was approved by the Department of Clinical Investigation at William Beaumont Army Medical Center in El Paso, TX. Six pigs, 6 to 10 weeks old, weighing 12 to 20 kg, were used in the study. The pigs were anesthetized with ketamine 22 mg/kg intramuscularly. Peripheral IV access was then obtained in the ear and butorphano10.2 mg/kg and promazine .15 mg/kg IV were administered. Throughout the study, supplemental diazepam IV was administered to augment the depth of anesthesia. An 18-gauge catheter was placed in the femoral artery of the leg opposite to that of the IO line. Mean arterial pressure (MAP) and cardiac monitoring were observed continuously. Two groups of three pigs were studied using the IO or IV route. The same animal was studied using the alternative route 48 hours after the initial trial. The trials were performed as crossovers, with one an IV group and the other an IO group in the first trial. Thus the pigs served as their own control. Intraosseous access was obtained through the medial tibia, one centimeter distal to the tibial tuberosity. An 18gauge spinal needle with stylet was introduced into the bone at a 90 degree angle using a downward pressing and twisting motion as described by Rogers and Benumof.6 The needle was advanced into the marrow cavity, identified as a decreased resistance to insertion. The stylet was then removed 181

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and the needle placement confiied by an aspiration of the marrow contents. Saline, 10 mL, was injected into the marrow to confirm patency of the needle and remove any clots. Intraosseous access was usually achieved within 30 seconds. Placement was successful in all animals on the first attempt and in no animal was there evidence of infiltration. Intravenous access for injection of phenytoin was obtained with a 20-gauge angiocatheter in an ear vein. Phenytoin, 15 mg/kg, was infused through the IO or IV site over a 15 minute period. An IMED Volumetric 928 Infusion Pump (IMED Corp, San Diego, CA) was used for the infusion to assure a consistent flow of 1 mg/kg/min and reduce the hypotensive response to phenytoin. Serum phenytoin levels were drawn from the femoral artery catheter 5, 10, 15, 20, 25, 30, and 35 minutes after infusion initiation. Serum samples were refrigerated for 24 hours and phenytoin levels were then determined by fluorescent polarization immunoassay using an Abbot TDX analyzer (Abbot Industries, N. Chicago, IL). Analysis of variance of repeated measures was used to evaluate statistical significance. The IO insertion site was marked with suture for later identification. Five weeks postinfusion the pigs were killed using pentobarbitol, 60 mg/kg IV. Sections were performed and slides made of the cortex and marrow at the IO site and contralateral noninvaded tibia. These sections were evaluated by a staff pathologist who was instructed. to look for signs of inflammation or decreased cellularity. The two tailed t-test was used to determine if there was a statistically significant difference in the amount of hematopoietic cells in the tibia bone marrow that received the IO infusion and the contralateral side. Because the IO site was marked with suture the pathologist was not blinded. This insured that the actual infusion site would be examined. RESULTS The serum phenytoin levels for pigs 1 through 6 are shown for the IV group and the IO group in Figures 1 and 2, respectively. Preinfusion phenytoin levels were drawn before the second trial for each pig; the highest level was 2.6 p/mL. These levels were subtracted from later postinfusion levels before statistical analysis. Trials were performed as crossovers to minimize the effect that this could instill in the results.

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FIGURE 2. Serum phenytoin levels following IO infusion, in +g/mL for pigs 1 through 6 over 35 minutes. VI0 = 1, 0 IO = 2, 010 = 3, 010 = 4, AI0 = 5, 010 = 6.

A larger degree of variability is seen in the IO group compared with the IV group. Although each of the pigs attained therapeutic phenytoin levels (10 pg/mL to 20 p/mL) during the IV trial, only three pigs attained this level during the IO trial. The reason for this is unknown; however, it could be explained by a binding of the phenytoin to the marrow contents. Mean phenytoin levels in CL/mL + / - 1 SD for both the IV and IO group are shown in Table 1. Mean levels for each group attained therapeutic serum phenytoin levels at the 15 mgikg dosage, although the IO group dropped below 10 I.L/mLpostinfusion (Fig 3). The mean phenytoin levels for the IV group were higher than those for the IO group; however, when the levels for both groups over 35 minutes were compared using analysis of variance repeated measures, the difference between the two groups was not statistically significant (P = .160). This trend has been shown in previous studies using other medication.7*a There was no effect demonstrated on blood pressure or heart rate by phenytoin infusion. Examination of the tibias of the pigs 6 weeks after the IO infusion showed the marrow on the side of the IO infusion to contain a mean level of 43% (SD = 26) hematopoietic cells whereas the opposite side contained a mean level of 26% (SD = 22) hematopoietic cells. Statistical analysis using the two tailed t-test shows this difference was not statistically significant (P = .29). There was no evidence of inflammation at the site of the IO line. DISCUSSION Our results show that the IO administration of phenytoin is an acceptable alternative to IV administration when IV access is not possible. Substances injected into the bone TABLE 1. Mean Levels of Phenytoin in pg/mL at 5 Minute Intervals After Infusion Time (min)

FIGURE 1. Serum phenytoin levels following IV infusion, in pg/mL for pigs 1 through 6 over 35 minutes. +IV = 1, XIV = 2, l IV = 3, WV = 4, AIV = 5, +IV = 6.

5

10

15

20

25

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Intravenous 9rw (SD)

10.4 (2.73)

14.5 (1.78)

17.3 (3.38)

12.4 (1.23)

11.6 (1.10)

11.0 (1.16)

11.0 (1.35)

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8.9 (4.14)

10.9 (4.38)

12.3 (6.58)

9.5 (4.50)

9.1 (4.0)

8.9 (4.28)

8.5 (3.70)

VINSEL, MOORE, AND O’HAIR n INTRAOSSEOUS PHENYTOIN IN PIGS

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The IO line is a quick, effective route for infusion of fluids or medications in pediatric emergencies. We have shown, in a series, that phenytoin loading exhibits similarly shaped pharmacological curves that are not statistically different when the intraosseous and intravenous routes are compared. Although initial phenytoin levels were therapeutic in the IO group, they dropped to subtherapeutic levels after 20 minutes. Thus a slightly higher loading dose of phenytoin may need to be used when IO infusion is used. Intraosseous infusion of phenytoin produces no permanent effects on the marrow.

FIGURE 3. Mean serum phenytoin levels following IV and IO infusion, in hg/mL for pigs 1 through 6 over 35 minutes.

The authors wish to thank Steve Stephenson, MD, and Raj Shekar, MD, for their assistance with the completion of this study.

marrow travel through the sinusoids and medullary veins, to nutrient and emissary veins, and into the systemic venous systeme4 This results in rapid systemic circulation of the medication. Tocantins noted the appearance of Congo red dye in the heart 10 seconds after IO administration in the tibia. 3 Intraosseous infusion of many substances has been reported either in case reports or in controlled animal trials. These include standard IV fluids such as DSW, normal saline, and Ringer’s lactate. Medications infused intraosseously include epinephrine, atropine, lidocaine, dopamine, dobutamine, diazepam, phenobarbital, sodium bicarbonate, dexamethasone, heparin, diazoxide, succinylcholine, ampicillin, calcium gluconate, and others.2*3*7T’6 Dilantin may be useful in patients with head trauma, status epilepticus, tricyclic antidepressant overdose, and digitalis toxicity. In 1986 Walsh-Kelly et al reported the case of a 2-year-old boy presenting to the emergency department in status epilepticus.’ After multiple unsuccessful attempts at peripheral IV access an 18-gauge Rosenthal needle was placed in the right anterior tibia. The patient received 17 mg/kg phenytoin sodium through the IO line at 25 mg/min followed by a bolus of 17 mL/kg of lactated Ringer’s solution. After the infusion the patient returned to his normal level of consciousness. Serum phenytoin level, drawn 140 minutes after infusion, was 28 I*JmL. We have confirmed successful loading of phenytoin IV in a series of animals. Complications of IO infusion are rare; the most common are osteomyelitis and subcutaneous abscess. Injection of strongly alkaline substances has been shown to produce changes in the bone marrow of edema and to decrease cellularity that cleared within weeks.4 The phenytoin sodium solution currently used for IV administration has an alkaline pH of 12.0. We have shown that there is no effect on the bone marrow 5 weeks after IO phenytoin infusion. In our study there is a trend toward a slightly decreased serum phenytoin level at all times in the IO group. Higher loading doses may be required for IO phenytoin infusion if levels comparable to IV administration are desired.

REFERENCES 1. Kanter RK, Zimmerman JJ, Strauss RH, et al: Pediatric emergency intravenous access. Am J Dis Child 1986;140:132134 2. Tocantins LM, O’Neill JF, Jones HW: Infusions of blood and other fluids via the bone marrow. JAMA 1941 ;117:1229-1234 3. Tocantins LM: Rapid absorption of substances injected into the bone marrow. Proc Sot EXD Biol Med 1940:45:292-296 4. Rosetti VA, Thompson BM, Miller J, et al: lntraosseous infusion: An alternative route of pediatric intravascular access. Ann Emerg Med 1985;14:885-888 5. Walsh-Kelly CM, Berens RJ, Glaeser PW, et al: Intraosseous infusion of phenytoin. Am J Emerg Med 1986;4:523524 6. Rogers SN, Benumof JL: lntraosseous infusion. In Roberts JR, Hedges JR (eds): Clinical Procedures in Emergency Medicine. Philadelphia, PA, Saunders, 1985, pp 339-343 7. Brickman KR, Rega P, Guinness M: A comparative study of intraosseous versus intravenous infusion of diazepam and phenobarbital in dogs. Ann Emerg Med 1987;16:1141-1144 8. Prete MR, Hannan CJ, Burkle FM: Plasma atropine concentrations via intravenous, endotracheal, and intraosseous administration. Am J Emerg Med 1987;5:101-104 9. Macht DI: Studies on intraosseous injection of epinephrine. Am J Physiol 1943;38:269-272 10. 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 Mad 1985;14:1135-1140 11. Berg RA: Emergency infusion of catecholamines into bone marrow. Am J Dis Child 1984;138:810-811 12. Spivey WH, Unger HD, Lathers CM, et al: lntraosseous diazepam suppression of pentylenetetrazol-induced epileptogenit activity in pigs. Ann Emerg Med 1987;18:156-159 13. Brickman KR, Rega P, Guinness M: Comparison of intraosseous, intratracheal and central venous administration of lidocaine in pigs. Ann Emerg Med 1988;17:435 (abstr) 14. McNamara RM, Spivey WH, Sussman C: Pediatric resuscitation without an intravenous line. Am J Emera Med 1986:4:3133 15. McNamara RM, Spivey WH, Unger HD, et al: Emergency applications of intraosseous infusion. J Emerg Med 1987;5:97101 16. Valdes MM: lntraosseous administration in emergencies. Lancet 1977;1:1235-1236