Endotracheal bretylium tosylate in a canine model

ORIGINAL CONTRIBUTION bretylium tosylate, endotracheal administration; endotracheal administration, bretylium tosylate

Endotracheal Bretylium Tosylate in a Canine Model This study was conducted to determine whether bretylium tosylate (BT) is effectively and safely absorbed through the endotracheal route in the canine model. Eleven adult mongrel dogs were anesthetized with pentobarbital, were orally intubated, and had continuous blood pressure and electrocardiographic monitoring. Four dogs received 5 mg/kg BT, three dogs received 10 mg/kg BT, two dogs received 20 mg/kg BT, and two control dogs were given volumes of normal saline equal to those given the 5- and lO-mg/kg groups. Each dog received the same dose of BT both endotracheally and intravenously, but in a random order and on different dates. Following each drug administration arterial blood was drawn at various intervals over two hours and sent for immediate gas analysis; serum samples were frozen for future determination of BT levels. Regardless of the amounts delivered, the peak levels of BT in the arterial blood following administration by the endotracheal route were consistently low (4.13 btg/mL to 14.00 Fg/mL) when compared to those levels following intravenously administered BT (120 b~g/ mL to 268 Fg/mL) (all P < .002 for the 5- and lO-mg/kg groups). No depot effect was observed during a two-hour period. The arterial blood gases did not change significantly following the administration of BT by the endotracheal route in the 5- and IO-mg/kg groups, and sections of these autopsied dog lungs showed no apparent pathologic changes. [Murphy KM, CapIen SM, Nowak RM, Lin W-N, Kelly AR, Slocombe R, Tomlanovich MC: Endotracheal bretylium tosylate in a canine model. Ann Emerg Med February 1984;13:87-91.]

INTRODUCTION Bretylium tosylate (BT), a bromobenzyl quaternary a m m o n i u m compound, 1 is recommended in the revised American Heart Association (AHA) treatment algorithm for countershock-resistant ventricular fibrillation. 2 Indeed, many authors have recommended its early use in the treatment of ventricular fibrillation during cardiopulmonary resuscitation. 3-5 A n u m b e r of drugs (atropine,6, 7 diazepam, s epinephrine,7, 9-13 lidocaine,7,14, is and naloxone 16) have been studied clinically and/or experimentally for their effectiveness when given by the endotracheal (ET) route. Endotracheal administration has obvious benefits when there is difficulty in obtaining venous access (ie, in infants, drug abusers, obese patients, and others). In fact, the remarkable absorptive capability of the lung has made the ET route the alternate method recommended by the AHA for delivery of epinephrine in cardiopulmonary resuscitation. 2 This study was performed to evaluate whether bretylium tosylate could be effectively absorbed in the canine model when delivered by the endotracheal route. Further, arterial blood gas analyses were obtained to assess any functional derangement in gas exchange caused by BT In addition, both gross and microscopic studies were performed on the autopsied canine lungs to determine any pathologic effects of this drug.

Kathleen M Murphy, MD* Stuart M Caplen, MD* Richard M Nowak, MD, FACEP* Wen-Nuei Lin, PhDt Annetta R Kelly, PhDt R Slocombe, BVSc, MS, PhD:~ Michael C Tomlanovich, MD, FACEP* Detroit, Michigan From the Department of Emergency Medicine* and the Division of Pharmacology/Toxicology, t Henry Ford Hospital, Detroit; and the Department of Pathology,* Michigan State University, East Lansing, Michigan. Presented at the University Association for Emergency Medicine Annual Meeting in Boston, June 1983. Received for publication July 14, 1983. Accepted for publication September 15, 1983. Address for reprints: Richard M Nowak, MD, Department of Emergency Medicine, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.

MATERIALS AND METHODS Eleven conditioned adult mongrel dogs weighing between 21 kg and 30 kg were anesthetized with 30 mg/kg intravenous sodium pentobarbital. The dogs were then orally intubated with a cuffed #9 endotracheal tube and al13:2 February 1984

Annals of Emergency Medicine

87/25

ET BRETYLIUM N o w a k et al

120

120

100

100

80

80

2oL__

~

-~6o

4O

40

.25.75 1.50

3

8o

20 lo 3-0

5

&

,

90

120

.25.75 1.50

3

10 30

60

90

120

MINUTES

MINUTES

3oo

3ooiT 200

-p

5

[

200-

I

180[

180

160[

160 140

;=L

120

"~ 120

lOO {

-'l 100

80

[

80

60

60

40

4O

20

20 ~-3[ . . . . . . . . . .

0

.25.75 1.50

10 30

5

80

90

_.a 120

0

.25.75 1.50

MINUTES

Fig. 1. Comparison of mean blood

concentrations of bretylium tosylate following 5-mg/kg intravenous (A) and endotracheal (B) administration. Fig. 2. Comparison of mean blood concentrations of bretylium tosylate following lO-mg/kg intravenous (A) and endotracheal (B) administration. lowed to breathe spontaneously. A peripheral cephalic foreleg vein was cannulated with a #18 intracath (Travenoll and an intravenous infusion of Ringer's lactate was established at a maintenance fluid rate. Bilateral percutaneous femoral artery cannulation was established for drawing blood samples and arterial blood gases, and 26/88

for continuous measurements of arterial blood pressure (Gould P23ID transducer and Gould Brush 260 polygraph recorder). Cardiac activity was continuously monitored using a Gould Brush 260 electrocardiograph recorder, while the temperature was monitored using a YSI Tele-thermometer rectal probe. Four dogs received 5 mg/kg of BT, three dogs received 10 mg/kg, ar;d two dogs received 20 mg/kg. One dog each received similar volumes of normal saline as did the 5-mg/kg and the 10mg/kg bretylium-treated animals, and acted as our controls. Each dog randomly received the drug either endotracheally or intravenously (IV) the first week, and after a m i n i m u m of Annals of Emergency Medicine

--

3

5 10 30 MINUTES

60

90

one week the same dog received the same dose of BT by the alternate route. Following each drug administration, blood levels for bretylium tosylate were drawn from the femoral artery, at 0, 0.25, 0.75I 1.50, 3, 5, 10, 30, 60, 90, and 120 minutes. During this t i m e continuous measurements of arterial blood pressure and cardiac activity were recorded. Further, arterial blood gases were drawn from the same arterial line at 0, 1, 5, 60, and 90 minutes. The drug used in the experiment was the commercially available 10-cc vial (50 mg/cc) of bretylium tosylate in water (Bretylol ®, American Critical Care Inc). 17 The intravenous BT was 13:2 February 1984

180 160

150

140

140

120

120

lOO

100

~ 80

ca 8 0

60

50

4O

40

20

20

0

2 5 . 7 5 1.50

5 MINUTES

delivered as a rapid bolus injection (2 to 12 cc).17 The technique of ET administration involved drawing up the predetermined amount of drug or control into a 20-cc syringe with a 5- to 10-cc air column behind it. The syringe was then attached to the proximal end of the flexible N-Do-Med (Ackrad Labs, Garwood, NJ), which was then placed so that its tip (with its multiple, minute openings) was just distal to the endotracheal tube. The solution was forcibly sprayed at end expiration through the catheter into the lung. The syringe and N-DoMed were then quickly removed and the open end of the ET tube was immediately occluded with a gloved finger to prevent regurgitation from any reflex coughing. I m m e d i a t e l y , ten quick insufflations with an Ambu Bag were performed at a rate of approximately one per second. All arterial blood gas analyses were performed using an American Institutional Lab Blood Gas Analyzer. Blood samples for d e t e r m i n a t i o n of bretylium levels were centrifuged in an IEC Clinical Centrifuge at 2,000 rpm for seven minutes. The serum was extracted, frozen, and then assayed for bretylium levels using a new technique of high pressure liquid chromatography (W-N Lin, AR Kelly, unpublished data, March 1982). After having received the drug by both IV and ET routes, the dogs were transported to the Michigan State University Veterinary Hospital for autopsy by Slocombe et al, at intervals 13:2 February 1984

•

' . 10 3 0

.

. 60

. 90

120

0

T-+--

,~ .....

.25.75 1.50

I .......

3

of one day to one week. The statistical methods used were the analysis of variance of repeated measures and the paired t test, as appropriate. RESULTS The arterial blood concentrations of BT after IV and ET administration are compared (Figures 1, 2, and 3). Maxi m u m concentrations following IV injection were achieved at approximately 15 seconds. The m a x i m u m levels achieved following ET administration were m o r e variable, but peaked between 15 and 90 seconds. (Approximately 10 seconds elapsed between the ET instillation of BT and the subsequent tenth forced ventilation.) All peak arterial blood levels of BT following ET a d m i n i s t r a t i o n were consistently low (4.13 ~/mL to 14.00 ~g/mL) when compared to those after IV delivery (120 i~g/mL to 268 ~g/mL) (all P < .002 for the 5- and 10-mg/kg groups). No depot effect was observed with ET administration during a twohour period. Although peak serum levels were similarly rapidly obtained with both routes, those following IV injection were 18 to 29 times greater. The blood BT levels generally fe'll rapidly after IV administration, usually by at least one quarter of the original peak concentration after 45 seconds. This fall continued, and after two hours all dogs had serum levels of less than a hundredth of the peak level. A n n a l s of E m e r g e n c y

Medicine

.-;~

..................

5 MINUTES

10 30

60

90

120

Fig. 3. Comparison of mean blood

concentrations of bretylium tosylate following 20-mg/kg intravenous (A) and endotracheal (B) administration. The usual h e m o d y n a m i c changes (initial hypertension followed by hypotension) following rapid intravenous administration of BT were seen inconsistently during the experiment. However, following ET delivery few hemodynamic changes of any kind were observed. The mean arterial PaO2, PaCO2, and pH in the 5- and 10-mg/kg groups did not significantly change from baseline values (Table 1). However, one of the 20-mg/kg animals (dog 10) became increasingly hypoxic (PaO~, 52), hypercarbic (PaCO2, 55) and acidotic tpH, 7.17) after receiving 12 cc BT by the ET route. The only significant pathologic finding after autopsy was a resolving bronchopneumonia in a control animal receiving ET normal saline. Five of the remaining ten dogs were found to have some focal accumulations of lymphocytes and macrophages that contained a foamy brown material and were adherent to bronchial lumens. This was interpreted as being suggestive of an intrapulmonary exposure to a fairly innocuous substance. DISCUSSION Endotracheal a d m i n i s t r a t i o n has been shown to be an effective method 89/27

ET BRETYLIUM Nowak et al

of drug delivery in both the animal model and the h u m a n cardiac arrest setting. 6-16 Indeed, the new advanced cardiac life support (ACLS) guidelines recommend endotracheal administration of epinephrine for those arrested patients in whom venous access cannot be readily established. 2 Bretylium tosylate, a bromobenzyl quaternary ammonium compound 17 (Figure 4), is currently r e c o m m e n d e d as initial antifibrillatory therapy for countershock-resistant ventricular fibrillation. ~ Many investigators have commented on the efficacy of the drug and have noted that its early use appears to be related to a more favorable outcome.a, 4 In our canine model, it is evident that bretylium tosylate is not well absorbed through the lung after ET administration, for peak levels were extremely low when compared to those obtained after IV administration. We think that these levels are so low as to be therapeutically insignificant, even though therapeutic levels of BT have not yet been adequately determined. 18 This failure to achieve adequate blood levels after ET administration differentiates BT f r o m other previously studied drugs, such as epinephrine, hU lidocaine,7 atropine,6, 7 naloxone, 16 and diazepam, s The molecular weight of BT (410) should not preclude its absorption by the lung; however, its p o s i t i v e charge and ionized form cause it to have low lipid solubility and thus less ability to penetrate the lipid-rich alveolar capillary membrane.l, is The minimal absorption seen is probably secondary to perm e a t i o n of quaternary a m m o n i u m compounds through aqueous pores in this membrane. Lipid-insoluble compounds studied in mouse, rat, and rabbit models have shown variable absorption rates, suggesting speciesspecific porosity characteristics39 Endotracheal absorption of the quaternary amine bretylium, then, may be different in the h u m a n lung w h e n compared to that of the dog. Although a secretory mechanism for quaternary ammonium compounds has been observed in the isolated guinea pig intestine, 2o the possible pulmonary absorption and subsequent secretion of these compounds has not been established. Endotracheally administered atropine, lidocaine, and epinephrine are noted to have extended durations of action, or a depot effect.7,n In our experiment, however, BT levels neither reached a serum concentration corn28/90

TABLE. PaO 2,

PUG02, and pH in dogs receiving ET bretylium tosylate Time (min) After ET Delivery

Amount Delivered 5 mg/kg (n = 4)

0 (base line)

1

5

60

90

79.3 31.0 7.29

76.5 35.7 7.28

76,8 36.0 7.28

79.5 33.3 7.29

80,1 34.8 7.27

73,3 40.0 7.29

72.6 40.3 7,31

72,0 34,3 7.27

92.0 33.3 7.30

75.0 37.3 7.27

PaO 2 (mm Hg) PaCO 2 (mm Hg) pH

10 mg/kg (n = 3)

PaO2 (mm Hg) PaCO 2 (ram Hg) pH All P > .05 by analysis of variance.

Fig. 4. Chemical structure of bre-

tyliLlm.

parable to those achieved after IV administration nor showed any characteristics of a depot effect. The therapeutic and toxic serum levels of BT have not been adequately established. 18 The highest level recorded in man after a single intravenous bolus (30 mg/kg) was 8,800 ng/ mL obtained three hours after administration. 21 Peak blood levels would assuredly have been t r e m e n d o u s l y higher. Following ET administration, the highest serum level of BT reported in our study was 14 Ixg, or 14,000 ng/ mL, and this was observed 15 seconds after administration. The highest level achieved following intravenous adm i n i s t r a t i o n was 268 ~g/mL, or 268,000 ng/mL, also after 15 seconds, seen in one of the 10-mg/kg animals. Detailed pharmacokinetic studies of BT have not been done; however, virtually all animal and human studies have used venous samples obtained within minutes to hours of BT administration.21, 22 In our experiment, arterial samples were drawn within 15 seconds of drug delivery, thus accounting for comparatively higher levels. Intravenous epinephrine is rapidly metabolized in the peripheral blood.it The inability of BT to be recovered in the serum theoretically could be due to its biochemical degradation at the alveolar capillary interface. The lung has been shown to contain m a n y enzymes that may metabolize a parent compound. It is possible that apparently poor absorption could be Seco n d a r y to u n a s s a y e d b r e t y l i u m tosylate metabolites. 2a However, bretylium normally is excreted almost entirely in the urine with 90% of it remainIng unchanged38, 24 Annals of Emergency Medicine

CH 3 CH2- + N - CH2--CH3

4

It is likely that the poor pulmonary absorption of BT is secondary to its i n t r i n s i c c h e m i c a l s t r u c t u r e and lipophobic nature.i, 18 These properties have been used in developing o t h e r t r e a t m e n t s . For e x a m p l e , ipratropium bromide, a quaternary isopropyl derivative of atropine, was developed for inhalation therapy of acute bronchial asthma. It is also poorly lipid soluble and not well absorbed, and thus does not have the systemic side effects that are seen with atropine. 25 It is possible that further i n c r e m e n t a l increases in the amount of BT given could cause more absorption through the lung and produce a therapeutic clinical effect. However, at its current concentration, the volumes of drug required would probably impair pulmonary function. Bretylium tosylate is commercially available in water. 17 Other investigators have commented that agents dissolved in water are more rapidly absorbed than are those dissolved in normal saline.26,~7 It is only w i t h larger volumes (ie, 2 cc/kg) that administration of water becomes more problematic when compared to normal saline.~8,~9 In our experiment, the volumes used were much below these levels, and theoretically the water should have enhanced bretylium absorption. The arterial blood gas analyses of 13:2 February 1984

those dogs receiving small volumes of ET BT (5 mg/kg, 10 mg/kg) showed no significant c h a n g e f r o m b a s e l i n e . These findings a p p r o x i m a t e those of Barsan et al, s w h o u s e d s i m i l a r l y small volumes w i t h diazepam. However, one of the dogs receiving 20 mg/ kg of ET BT (12 cc) suffered deterioration of arterial blood gases. It is thus possible that gaseous exchange in the canine model can be impaired w i t h as little as 12 cc of fluid delivered by the ET route. To date, none of the experimental studies in animal or m a n has investigated the effect of intrapulmonary drugs on lung pathology. The detailed pathologic studies of our bretylium-treated autopsied dogs revealed no s i g n i f i c a n t a b n o r m a l i t i e s . T h e foamy brown material seen most likely represented p h a g o c y t i z e d surfacrant. CONCLUSIONS B r e t y l i u m t o s y l a t e is p o o r l y absorbed through the endotracheal route in the a n e s t h e t i z e d c a n i n e m o d e l . This is p r o b a b l y due to t h e drug's lipophobic nature and its inability to effectively cross the alveolar capillary membrane. T h u s a d m i n i s t r a t i o n of bretylium tosylate by the endotracheal r o u t e w i l l p r o b a b l y n o t be useful d u r i n g c a r d i o p u l m o n a r y resuscitation. As other antiarrhythmics are considered for d e l i v e r y t h r o u g h the e n d o t r a c h e a l r o u t e , a t t e n t i o n should be g i v e n to t h e i r c h e m i c a l structure and lipid solubility. The authors thank Ms Marty Racey for her assistance in the preparation of this manuscript.

REFERENCES 1. Bigger JT, Hoffman BF: Antiarrhythmic drugs, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics, ed 6. New York, MacMillan, 1980, p 761-792. 2. Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). JAMA 1980;244:453-509.

13:2 February 1984

3. Harrison EE, Amey BD: The use of bretylium in prehospital ventricular fibrillation. American Journal of Emergency Medicine 1983;1:1-6. 4. Nowak RM, Bodnar TJ, Dronen S, et al: Bretylium tosylate as initial treatment for cardiopulmonary arrest: Randomized comparison with placebo. Ann Emerg Med 1981;10:404-407. 5. Koch-Weser J: Drug therapy: Bretylium. N Engl J Med 1979;300:473-477. 6. G r e e n b e r g MI, M a y e d a DV, Chrzanowski R, et ah Endotracheal adm i n i s t r a t i o n of atropine sulfate. Ann Emerg Med 1982;11:546-548. 7. Elam J: The intrapulmonary route for CPR drugs, in Safar P (ed): Advances in Cardiopulmonary Resuscitation, ed 1. New York, Springer-Verlag, 1977, p 132-140. 8. Barsan WG, Ward JT, Otten EJ: Blood levels of diazepam after endotracheal administration in dogs. Ann Emerg Meal 1982;11:242-247. 9. Roberts JR, Greenberg MI, Baskin SI: Endotracheal epinephrine in cardiorespiratory collapse. JACEP 1979;8:515519. 10. Greenberg MI, Roberts JR, Krusz JC, et ah Endotracheal epinephrine in a canine anaphylactic shock model. JACEP 1979;8:500-503. 11. Roberts JR, Greenberg MI, Knaub MA, et al: Blood levels following intravenous and endotracheal epinephrine administration. JACEP 1979;8:53-56. 12. Roberts JR, Greenberg MI, Knaub M, et ah Comparison of the pharmacological effects of epinephrine administered by the intravenous and endotracheaI routes. JACEP 1978;7:260-264. 13. Greenberg MI, Roberts JR, Baskin JI: Use of endotracheally administered epinephrine in a pediatric patient. A m J Dis Child 1981;135:767-768. 14. Viegas O, Stoehing RK: Lidocaine in arterial blood after laryngotracheal administration. Anesthesiology 1975;43: 491-493. 15. Chu 8S, Rah KH, Brannan MD, et ah Plasma concentration of lidocaine after endotracheal spray. Anesth Analg 1974; 54:438-441.

Annals of Emergency Medicine

16. Greenberg MI, Roberts JR, Baskin 8I: Endotracheal naloxone reversal of morphine-induced respiratory depression in rabbits. Ann Emerg Med 1980;9:289-292. 17. Bretylol (bretylium tosylate) injection. Revised package insert. McGaw Park, IL, American Critical Care, Inc, 1980. 18. Anderson JL: Bretylium: An update on pharmacokinetic studies and clinical uses, in Rapaport E (ed): Cardiology Update: Reviews for Physicians. New York, Elsevier Biomedical, 1983, p 241-263. 19. Schanker LS: Drug absorption from the lung (commentary}. Biochem Pharmacol 1978;27:381-385. 20. Turnheim K, Lauterbach FO: Absorption and secretion of monoquaternary ammonium compounds by the isolated intestinal mucosa. Biochem Pharmacoi 1977;26:99-108. 21. Bodnar T, Nowak RM, Tomlanovich MC: Massive intravenous bolus bretylium tosylate. Ann Emerg Med 1980;9: 630-633. 22. Kamath BL, Gibson TP, Look ZM, et ah Pharmacokinetics of bretylium in dogs and the effect of hemoperfusion on its e l i m i n a t i o n . J P h a r m Sci 1982;71: 1294-1296. 23. Fishman AP, Pietra GG: Handling of bioactive materials by the lung. N EngI J Med 1974;291:953-959. 24. Bryan KB, Darby MH: Bretyfium tosylate: A review. A m J Hosp Pharm 1979; 36:1189-1191. 25. Rebuck AS, Chapman KR, Braude AC: Anticholinergic therapy of asthma. Chest 1982;82:55S-57S. 26. Redding JS, Asuncion JS, Pearson JW: Effective routes of drug administration during cardiac arrest. Anesth Analg 1967; 46:253-258. 27. Courtice FC, Phipps PJ: The absorption of fluids from the lungs. J Physiol 1946;105:186-190. 28. Ward JT: Endotracheal drug therapy: Research seminars. American Journal of Emergency Medicine 1983;1:71-81. 29. Greenberg MI, Baskin SI, Kaplan AM, et ah Effects of endotracheally administered distilled water and normal saline on the arterial blood gases of dogs. Ann Emerg Med 1982;11:600-604.

91/29