Systemic absorption of epinephrine after endoscopic submucosal injection in patients with bleeding peptic ulcers

0016-5107/93/3901-0020$1.00 + .10 GASTROINTESTINAL ENDOSCOPY Copyright © 1993 by the American Society for Gastrointestinal Endoscopy

Systemic absorption of epinephrine after endoscopic submucosal injection in patients with bleeding peptic ulcers Joseph Y. Sung, MBBS, MRCP(UK), PhD, Sydney C.S. Chung, MD, FRCS, MRCP(UK) John M. Low, BM BCh, FFARCS, R. Cocks, FRCS S.M. Ip, PhD, Pet Tan, BSc, Joseph W.C. Leung, MD, FRCP(Edin) T.E. Oh, MD, FRCP, FFARCS, Arthur K.C. Li, MD, FRCS, FRACS, FACS Hong Kong

Epinephrine injection is an effective, simple, and economical method of endoscopic hemostasis for bleeding peptic ulcers. We measured catecholamine levels in 18 patients with actively bleeding ulcers (8 gastric ulcers and 10 duodenal ulcers) treated by endoscopic injection. Injection of epinephrine (1:10,000 IU) was given until bleeding from the ulcers stopped. Catecholamine levels were assayed by high-pressure liquid chromatography. Immediately after the injection the plasma level of epinephrine rose by four to five times above the basal level and returned to the baseline in 20 minutes. Norepinephrine levels were not significantly raised in these patients. No cardiovascular complications were seen. Although adverse cardiac events have not been recorded, it seems prudent to monitor these patients closely during and immediately after epinephrine injection. (Gastrointest Endosc1993;39:20-22.)

Among the various methods of endoscopic hemostasis for bleeding peptic ulcers, epinephrine injection has been gaining popularity because it is economical and simple to use.!' 2 A randomized trial comparing epinephrine and heat probe has shown that epinephrine injection is at least as good as the thermocoagulation hemostasis method in controlling bleeding from peptic ulcers. 3 Rugeerts et a1. 4 have shown that epinephrine plus polidocanol gives even better results in the control of bleeding and advocated this as the treatment of choice. One of the major concerns regarding injection therapy is the safety of epinephrine. Although cardiovascular complications have not been reported, information on systemic absorption of submucosally injected epinephrine is lacking. The purpose of this study was to investigate the pharmacokinetics of submucosal epinephrine injection in the gastrointestinal tract.

1000 900

i

800

1!1

600

~ <:

500

>

'E

.!ll 0

Nor-epinephrine (me.n+SEM)

700

400

.<:

v

.2

'"

Epinephrine (mean+SEM)

300

()

200

100

a Be10re

10

15

20

25

30

35

Time after Injection (min)

Figure 1. Catecholamine levels after endoscopic injection of epinephrine. Levels were significantly higher (p < 0.05) at 0, 2, 5, and 10 minutes.

Received March 18, 1992. For revision May 7, 1992. Accepted July 15,1992.

From the Departments of Medicine, Surgery and Anaesthesia, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong. Reprint requests: Dr. Joseph Y. Sung, Department of Medicine, Prince of Wales Hospital, Hong Kong. 37/1/43154

20

PATIENTS AND METHODS

Eighteen patients with actively bleeding ulcers at the time of endoscopy were recruited in the study. The group comprised 17 men and 1 woman, with ages ranging from 30 to 68 years (median, 52 years). Eight patients had bleeding from gastric ulcers, and 10 had bleeding from duodenal ulcers. GASTROINTESTINAL ENDOSCOPY

Table 1. Plasma epinephrine and norepinephrine levels in 18 patients Epinephrine/ 2 min Pre-injection o min norepinephrine

5

min

Epinephrine (pg/ml; 165 ± 39 618 ± 103* 349 ± 73* 261 ± 35* mean ± SEM) Norepinephrine 726 ± 44 799 ± 99 828 ± 104 667 ± 80 (pg/ml; mean ± SEM) *Epinephrine level significantly higher (p < 0.05) than the pre-injection level. tNorepinephrine level significantly lower (p < 0.05) than the pre-injection level.

Among these ulcers, 4 were spurting and 10 were actively oozing at the time of endoscopy. Five patients were in shock (systemic blood pressure <90 mm Hg and pulse> 100 beats/ min) on admission. Xylocaine 10% (total dose 100 mg) was given to provide local anesthesia to the throats of these patients before endoscopy. These ulcers were injected with epinephrine (1:10,000 IU) by using a flexible needle injector (Olympus NM-1K; Olympus Corp., Lake Success, N.Y.) inserted through the biopsy channel of the endoscope. Aliquots of 0.5 to 1 ml of epinephrine were injected by multiple punctures into and around the bleeding point until the bleeding stopped. Throughout the period of endoscopy and epinephrine injection, the patients were closely monitored by pulse oximeter (OxyShuttle, Criticon Inc., Tampa, Fla.) and automatic blood pressure monitoring (Dinamap, Criticon Inc.). After a bleeding ulcer was identified by endoscopy and the decision to perform epinephrine injection was made, 5 ml of venous blood was drawn from the patients immediately before the injection. Blood samples were then taken immediately after the injection (0 minutes) and 2, 5, 10, 20, and 30 minutes later. The blood samples were collected in lithium heparin tubes containing glutathione, stored on ice until the last sample was drawn, and then immediately spun down at 4 0 C. Plasma were stored at -70 0 C and then processed in batches. Samples were prepared by alumina extraction, and catecholamines were extracted using acetic acid. Epinephrine and norepinephrine were measured by high-pressure liquid chromatography using a reversed-phase ODS C18 column (Beckman, San Ramon, Calif.). Detection of the analylates were conducted by colometric detector. The lower limit of detection was 25 pg/ml. Epinephrine and norepinephrine levels were expressed as mean ± SEM. The levels of catecholamines were compared with the baseline level before the injection was given by using paired Student's t test. Statistical significance was taken at p < 0.05. The correlation between the volumes of epinephrine injected and the plasma levels of catecholamine were computed by Pearson's coefficient of correlation. RESULTS

Sixteen of 18 cases (88.9 %) of bleeding peptic ulcers in this series were controlled by a single session of endoscopic epinephrine injection. The volume of epinephrine used ranged from 3 to 11 ml, and the mean volume per session was 6.5 ml. Endoscopic hemostasis failed in two patients who had bleeding from a prepyloric ulcer. Both patients required emergency surgery to control their bleeding. No cardiovascular complication was reported in these patients. The five patients VOLUME 39, NO.1, 1993

10

min

20

min

30

min

222 ± 32*

152 ± 14

143 ± 18

565 ± 66t

552 ± 65t

515 ± 71t

who were in shock on admission were hemodynamically stabilized after the endoscopic hemostasis. No abrupt change occurred in blood pressure, pulse rate, or oxygen saturation of blood documented in these patients related to epinephrine injection. ECG monitoring in available cases did not record any cardiac arrhythmia after the injection. The plasma levels of epinephrine and norepinephrine are summarized in Table 1. Immediately after endoscopic injection of epinephrine, the plasma levels rose almost instantaneously to four to five times the pre-injection levels. The volume of epinephrine injected did not show significant correlation with the O-minute plasma levels in these patients (r = -0.12). The plasma epinephrine levels were significantly higher than the basal level in the first 10 minutes after the therapy (Fig. 1) (p < 0.05). Two patients in this series had very high plasma epinephrine levels (1854 pg/ml and 1194 pg/ml) at the O-minute samples after the injections (Fig. 2). Both ofthem have cirrhosis and hepatocellular carcinoma. Norepinephrine levels were not elevated after the injection and in fact were significantly lower than the preinjection levels at 10, 20, and 30 minutes after the endoscopy (Fig. 1). DISCUSSION

The local tissue effects of various hemostatic agents have been studied in an experimental model using dogs. 5 Ethanol and polidocanol produce submucosal tissue necrosis with vasculitis in ethanol and intense inflammation in polidocanol injection. Epinephrine produced the least tissue damage, which accounts for fewer perforations as compared with other hemostatic agents. 6 The hemostatic effect of epinephrine is probably related to vasoconstriction,7,8 pressure effect by the injected volume,5 and platelet aggregation. 9 Despite the lack of tissue damage at the site of injection, possible hemodynamic side effects from systemic absorption of epinephrine have been a cause for concern. Results from this study show that a significant amount of submucosally injected epinephrine was absorbed into the systemic circulation. The absorption of epinephrine from gastrointestinal mucosa occurred very rapidly. An average of a fourfold increase in the epinephrine level was detected almost instantaneously 21

2000

~

.*

1500

E 0>

.*

S

q,

>

.9Z q,

<: 'C

1000

.*

•

.<= 0-

•

q,

<: 0W

500

.*1* •

a

•

•

•

before

.* I

I

•••

••

I

Omin

2 min

•

Time after Epinephrine Injection

Figure 2. Serum epinephrine levels of individual patients after endoscopic epinephrine injections. *Indicates patients with hepatocellular carcinoma.

after injection. The peak level of epinephrine probably occurs somewhere between 0 minutes and 2 minutes. The drug is then rapidly removed from the circulation and returned to the basal level within 20 minutes. It is well known that catecholamines have a significant first-pass extraction by the liver. 10 In the two patients who had compromised liver function, the epinephrine levels in the systemic blood were understandably higher than in the other patients. Nevertheless, even when the two patients with cirrhosis were excluded, significant elevation of plasma epinephrine levels were still demonstable within the first 10 minutes after injection (p < 0.05). No direct relationship was seen between the volume of epinephrine injected and the amount absorbed. Spillage from the puncture site, difference in vascularity of the ulcer and the surrounding tissue, and differences in liver metabolism are possible explanations for this. Plasma concentrations of catecholamines vary widely, depending on physiologic or pathophysiologic conditions. The safety limits of catecholamine levels in blood are unknown and probably depend on individuals. Graded infusions of epinephrine into human beings showed that increased heart rate and systolic blood pressure is evident at 75 to 125 pg/ml.n A peak level of 600 pg/ml in our patients receiving adrenaline injection is comparable to some major stressful conditions, such as insulin-induced hypoglycemia, diabetic ketoacidosis, and myocardial infarction.l 2 However,

22

we did not record any cardiovascular complications. Two factors have to be considered. First, the elevated epinephrine levels in our patients were a very transient phenomenon; plasma epinephrine levels were elevated to above 200 ng/ml only in the first 5 minutes or so (Fig. 1). Second, it is well known that the presence of lignocaine will increase the threshold of ventricular arrhythmia. 13 During the endoscopic procedures, 10 % xylocaine spray was applied for topical anesthesia to the larynx; it has been established that a considerable amount oflignocaine may be absorbed from the laryngeal mucosa. 14 This may have contributed to the safety of the use of epinephrine. 15 In conclusion, significant amounts of submucosally injected epinephrine are absorbed into the systemic circulation. Although adverse cardiac events have not been recorded, it seems prudent to monitor these patients closely during and immediately after epinephrine injection.

REFERENCES 1. Chung SCS, Leung JWC, Steele RJC, Crofts TJ, Li AKC. Endoscopic adrenaline injection for actively bleeding ulcer: a randomized trial. BMJ 1988;296:1631-3. 2. Panes J, Viver J, Forne M, Garcia-Olivares E, Marco C, Garau J. Controlled trial of endoscopic sclerosis in bleeding peptic ulcers. Lancet 1987;2:1292-4. 3. Chung SCS, Leung JWC, Sung JY, Lo KK, Li AKC. Injection or heat probe for bleeding ulcer. Gastroenterology 1991;100: 33-7. 4. Rutgeerts P, Vantrappen G, Broechkaert L, Coremans G, Janssens J, Hiele M. Comparison of endoscopic polidocanol injection and YAG laser therapy for bleeding peptic ulcer. Lancet 1989;1:1164-7. 5. Rutgeerts P, Geboes K, Vantrappen G. Experimental studies of injection therapy for severe non-variceal bleeding in dogs. Gastroenterology 1989;97:610-21. 6. Nakagawa K, Asaki S, Sato T. Endoscopic treatment of bleeding peptic ulcers. World J Surg 1989;12:154-7. 7. Chung SCS, Leung FW, Leung JWC. Is vasoconstriction the mechanism of haemostasis in bleeding ulcers injected with epinephrine? A study using reflectance spectrophotometry. Gastrointest Endosc 1988;34:174-5. 8. Chung SCS, Leung JWC, Galvina M, Lee TW. The effect of submucosal adrenalin on blood loss from standard ulcers [Abstract). Gut 1987;128:AI402. 9. O'Brien JR. Some effects of adrenaline and anti-adrenaline compounds on platelets in vitro and in vivo. Nature 1963;200: 763-4. 10. Le Veen HH, Diaz C, Falk C, et al. A proposed method to interrupt gastrointestinal bleeding: preliminary report. Ann Surg 1972;175:459-69. 11. Clutter W, Bier D, Shah S, Cryer P. Epinephrine: plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 1980;66:94-101. 12. Cryer P. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303: 436-44. 13. Johnston RR, Eger EI, Wilson C. A comparative interaction of epinephrine with enflurane, isoflurane and halothane in man. Anesth Analg 1976;55:709-14. 14. Scott DB, Littlewood DG, Covine BG, Drummund GB. Plasma lignocaine concentrations following endotracheal spraying with an aerosol. Br J Anaesth 1976;48:899-903. 15. Low JM, Harvey JT, Cooper GM, Prendiville WJ. Plasma concentrations of catecholamines following adrenaline infiltration during gynaecological surgery. Br J Anaesth 1984;56:849-53.

GASTROINTESTINAL ENDOSCOPY