The role of thromboxane in experimental inadvertent intra-arterial drug injections

The role of thromboxane in experimental inadvertent intra-arterial drug injections Inadvertent intra-arterial injection of drugs produces a well-defined clinical syndrome whose pathophysiology remains unclear. This study was designed to determine the role of the inflammatory mediator, thromboxane, in intra-arterial drug injections. The rabbit ear model, as described by Kinmonth and Sheppard, was used. Five of the experimental groups were treated with specific or nonspecific thromboxane blocking agents and two groups served as controls. Immunohistochemical staining of the control ears showed elevated levels of thromboxane within the first 6 hours postinjury. The specific thromboxane blocking agents, methimazole and Aloe vera, showed almost complete blockade of thromboxane production. The percentage of ear survival was significantly greater in the group treated with topical Aloe vera (p < 0.05) and even greater survival was achieved in the combined Aloe vera/methimazole group (p < 0.01). On the basis of these results, we have begun treatment of such injuries with specific and nonspecific thromboxane blocking agents. (J HAND SURG 1987;12A:240-5.)

Lawrence S. Zachary, M.D., David J. Smith, Jr., M.D., John P. Heggers, Ph.D., Martin C. Robson, M.D., Jane A. Boertman, B.S., Xing-Tao Niu, M.D., Rodica E. Schileru, M.D., and Robert J. Sacks, B.S., M.S., Baltimore, Md., Detroit, Mich., and the Republic of China

Inadvertent intra-arterial injection of drugs produces a well-defined clinical syndrome whose pathophysiology remains unclear. Distal necrosis and endarteritis are coupled with an intense inflammatory reaction of the surrounding tissue that leads to a progressive ischemic injury with eventual tissue loss. Although vasospasm and particulate embolization of end arteries are the two most commonly accepted theories, 14 neither adequately explains the intense inflammatory reaction and swelling in the adjacent tissue. In addition, numerous methods of treatment based on these theories have not consistently proven effective: The progressive nature of this injury is similar to the progressive injury seen in the bum wound, frostbite, and the distal dying

From the Wayne State University School of Medicine, Detroit Receiving Hospital, 4201 SI. Antoine, Detroit, Mich. Received for publication Feb. 25, 1986; accepted in revised form June 17, 1986. This article was accepted for publication before July I, 1986. No conflict-of-interest statement was requested from the authors. Reprint requests: David J. Smith, Jr., M.D., Division of Plastic and Reconstructive Surgery, Room 4V-23, 4201 SI. Antoine, Detroit, MI48201.

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flap. Thromboxane, a vasoconstrictor and platelet aggregator, has been found to be a central mediator in these injuries."? Blockade of thromboxane production with specific or nonspecific antithromboxane agents has led to improved tissue survival in these conditions in both experimental and clinical studies. This study was designed to determine: (1) the role of thromboxane in intra-arterial drug injection injuries and (2) to determine if blockade of thromboxane with specific or nonspecific blocking agents would result in increased tissue survival and improve our clinical results.

Materials and methods The rabbit ear model described by Kinmonth and Sheppard was used." This model consistently shows necrosis distal to the site of sodium thiopental (Pentothal) injection and thus presented a reliable model to evaluate the role of thromboxane production after intraarterial drug injection injuries. All animals were weighed and anesthesized with xylene (5 mg/kg) and ketamine (35 mg/kg) intramuscularly. A cutdown was performed at the base of each ear and the central artery isolated. An arteriotomy was made and a l-inch 24-gauge silicone catheter was inserted distally into the artery (Fig. 1). The artery was

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ligated proximally and the catheter secured distally with a 6-0 silk tie. A 10% sodium thiopental (Pentothal) solution (15 mg/kg) was injected slowly over a 2-minute period. As the injection was given, the base of the ear was manually compressed to assure complete perfusion of the ear by preventing early venous runoff. After removing the cannula, the distal portion of the artery was ligated with a 6-0 silk tie. A template of each ear was made on clear x-ray film before each Pentothal injection. At the end of 21 days, each ear was redrawn on clear x-ray film and the percentage of ear survival determined by planimetry. Biopsy specimens were obtained from each ear in the zone of injury immediately after the Pentothal injection and at 6, 24, 48, and 72 hours postinjury. Specimens for a second biopsy were taken from the back of each animal to serve as a control biopsy in a noninjured area. All biopsies were fixed and stained for thromboxane using the Peroxidase anti-peroxidase technique." The degree of thromboxane deposition was graded from 0-4 + , with 0-1 + representing normal skin production of thromboxane and 4 + showing heavy production of thromboxane in an injured state. 9 Thirty-five New Zealand white rabbits were equally divided into seven groups. Two groups served as controls. Group I animals were injected with saline solution through the previously inserted intra-arterial ear catheter and received no further treatment. In contrast, group II animals were injected with Pentothal through the ear catheter and received no further treatment. This group served as a control model for the inadvertent intraarterial injury. Five groups were treated with either specific or nonspecific thromboxane blocking agents after an intra-arterial Pentothal injection similar to control group II. Methimazole and Aloe vera are specific blockers of thromboxane production while aspirin and methylprednisolone are nonspecific blocking agents." Group III received aspirin at 50 mg/kg intraperitoneally every 8 hours. Group IV received topical 1% methylprednisolone acetate every 6 hours. Group V received methimazole 1 mg/kg intraperitoneally every 8 hours. Group VI received topical Aloe vera every 6 hours. Group VII received topical Aloe vera every 6 hours and methimazole 1 mg/kg intraperitoneally every 8 hours. All animals were treated for 72 hours. Statistical analyses were performed by the Student Neuls multiple comparison test. Results Immunohistochemical stammg for thromboxane showed markedly increased levels of thromboxane in the control Pentothal injection group (group II) but no

Thromboxane in intra-arterial drug injections

241

Artery

42

min. infusion 10% pentothal (15 mg/kg)

Fig. 1. The rabbit ear model described by Kinmonth and Sheppard was duplicated. A 10% sodium thiopental (Pentothal) solution was injected over a 2-minute period.

increase after saline injection (group I). All treatment groups showed levels of thromboxane production below that of the control Pentothal injection group. In fact, the topical Aloe vera group, the methimazole group, and the combined Aloe vera and methimazole group had almost complete blockade of thromboxane production after 6 hours of therapy, while the control groups continued to have increased levels of thromboxane production (Table I). Although the percentage of ear survival was significantly greater in the group treated with topical Aloe vera alone (p < 0.05), even greater survival was achieved with the combined Aloe vera/methimazole group (p < 0.01) (Figs. 2 and 3). No other significant differences were found. Discussion In 1942, Van der Post" first described the events of an intra-arterial drug injection of thiopentone during anesthesia that resulted in the loss of three fingers. In an "exhaustive review of the literature, Cohen,": 13 in 1948 reported an additional 12 cases of inadvertent drug injections and summarized the treatment methods avail-

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Zachary et al.

MEAN RABBIT EAR SURVIVAL 110 100 90 80 .....l

70

~

50

~

=> (f) se

60

40

SAUNE

I

ALOE

METHIMAZOLE METHIMAZOLE pm IAlllOL .c<;PIRIN MEDROL ALOE

30 20 10

o-

GRP 1

GRP 2

GRP 3

GRP 4

GRP 5

GRP 6

GRP 7

Fig. 2. The greatest rabbit ear survival was achieved in the combined Aloe vera/methimazole treatment group VII (p < 0.01).

Fig. 3. A, Ear survival after Pentothal injection and treatment with combined Aloe vera/methimazole. B, Ear survival after Pentothal injection without treatment.

able. Therapeutic options included anticoagulation, sympathetic blockade , elevation , general anesthesia to induce vasodilation, rest , cooling of the affected limb, warming the patient except for the affected limb, vasodilator therapy, and surgical thrombectomy of the affected arteries . Results were rather dismal and salvage uncertain. In the past 37 years treatment has not changed significantly and continues to be on the basis of anecdotal experience . 14· 27 Although some recent studies have reported the use of thrombolytic agents to treat acute arterial occlusions in the hand and upper extrem-

ities, of the 16 reported cases, only two resulted from intra-arterial drug injections ." : 29 Both responded to thrombolytic therapy . The use of intra-arterial steroid infusion has also been suggested but no clinical trials have been reported. " The clinical picture noted acutely after intra-arterial drug injection includes burning pain on injection, cyanosis, skin mottling , and swelling of the skin and subcutaneous tissue distal and proximal to the site of injury, and occasionally vascular thrombosis of major vessels, which is a limb threatening emergency. Many

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Thromboxane in intra-arterial drug injections

Table I. Tiss ue thromboxane levels in intra-arteria l Pentothal NA

of-

+

243

injection Time

Treatment

(f'

Pentotha l Aspirin MEDROL Methimazole Dermaide aloe Aloe/methimazole Saline solution

2 2 2 2 2 2 I

I

6 hr

24 hr

48 hr

72 hr

4 3 3 1 2 I 0

4 2 2 I

3 I I I I 0 0

3 I 1 0 0 0 0

I I 0

Table II. Percentage tissue necrosis according to treatment groups Group No.

I II III

IV V VI VII

Treatment

% Necrosis (mean)

Standard deviatio n

Saline Pentothal Aspirin Medrol Methimazole Aloe Aloe/met himazole

0 .19 55.61 53.96 53.25 52.55 48 .78 ( p < 0 .05) 35.85 ( p < 0.01)

0 .81 10.14 6.61 8.4 2 6 .51 5. 29 7.10

of these patie nts need subseq uent amputations. Chronic problems include edema, abscess forma tion, gangrene, cold intolerance, nonhealing ulcer s, and joint stiffness . Since many patients who incur arterial injection injuries do not seek medical treatment immediately, treatment optio ns are often reduced and complications maximized. The pathophysio logy of acu te intra-arterial drug injection injuries remains unclear. Kinmonth and Sheppard" emphasized the importance of the concentration of thiope ntone and its direct irrita nt effect on the vesse l wall. Ellerto n and associates/ proposed venoconstriction as the mechanism of injury, while Bum championed noradrenalin release .3 1.32 Waters suggested arterial blockade of thiope ntone crystals.' Cohen 19 . 20 proposed that pH and toxic effects of thiopentone were most important. Brown and col league s" showed hemolysis of red cells and plate let aggregation after injection injuries . Wright and co-workers" showed how starch and talcum (two agents used in commonly abused drugs) caused microemboli and thrombosis of the microcirculation .' Despite these numerous theories , the consistent feature of progressive tissue necrosis remained unexplained. Buckspan et al ." observed the loss of intimal cells and the presence of interstitial edema within 90 minutes of injury . Red cell sludging was present within

3 hours. This was followed by increa sing interstitial edema up to 72 hours with early thrombosis and by 5 days , severe vessel necrosis, thrombosis , and adjacent soft tissue necrosis . Several studies"? have shown how the inflammatory mediators of the arachidonic acid cas cade can reduce this progressive injury. Experimental data has implicated thromboxane (a vasoconstrictor and potent platelet aggregator) to be a central mediator of the progressive tissue loss seen in the bum wound ," frostbite injury,' distal dying flap," and electrical burns ." It seemed only logical to test the hypothesis that the inflammatory mediators of the arachi donic acid cascade, and in particular thromboxane, would contribute to the progressive tissue loss after inadvertent intra-arterial drug injection injuries. Salicylates and steroids act as nonspecific inhibitors of thromboxane production . Aloe vera also contains a large quantity of salicy lates . In addition , although, Aloe vera contains emod in and emolin, both of whic h have been shown by Heggers and Robson'? and Penneys" to act as com petitive inhibitors of thromboxane synthetase. Therefore, Aloe vera specifically blocks thromboxane production. Methimazole has also been shown to be a specific inhibitor of thromboxane production. As previously shown by Kinmonth and Sheppard ," some contraction usually occurred in and arou nd the necrotic portion of the ear after intra-arteria l pentathol

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Zachary et al .

injection . They determined that tissue loss was most accurately assessed by measuring the area of injury in relation to the normal uninjured ear. Using these measurements, the progressive tissue loss seen in the rabbit ear model was partially abrogated by the use of specific thromboxane inhibitors (Table II). The combined use of the systemic antithromboxane drug methimazole and the topical antithromboxane agent Aloe vera provided significant improvement in tissue survival. Immunohistochemical staining of the treated tissues showed almost complete inhibition of thromboxane production. It appears the pathophysiology of intra-arterial drug injections can be broken down into two components. As shown by Wright and associates" and Waters/ microembolization of drug crystals and drug impurities (starch and talcum) into the microcirculation causes thrombosis of distal end vessels. This results in welldefined areas of tip necrosis but does not account for the proximal progressive tissue injury. On the basis of our experimental results, we believe this progressive proximal injury is mediated by thromboxane release. Thus, a specific antithromboxane blocking agent may be a beneficial adjunct for the treatment of intra-arterial drug injection injuries. REFERENCES I . Klatte C, Brooks L, Rhamy RK: Toxicity of intra-arterial barbiturates and tranquilizing drugs . Radiology 92:7004, 1969 2. Ellerton G, Lazarus HM , Auerba ch R: Patterns of acute vascular injury after intra-arterial barbiturate injection. Am J Surg 126:813-7 , 1973 3. Waters OJ: Intra-arterial thiopentone: A physiochemical phenomenon. Anesthesia 21:346-56 , 1966 4. Wright CB, Lamoy RB, Hopson RW II: Hemodynamic affects of intra-arterial injection of drug abuse. Surgery 79:425-31, 1976 5 . Raine TJ, London MD,Goluch L , et al: Antiprostaglandins and antithromboxanes for treatment of frostbite . Surg Forum 31:557 -9, 1980 6. Robson MC, Del Beccaro EJ , Heggers JP: Effect s of prostaglandins in the dermal microc irculation after burning and the inhibition of the effect by specific pharmacological agents . Plast Recon str Surg 63:781-7, 1979 7. Zachary LS , Robson MC, Heggers JP, et al: The role of arachidonic acid metabolites in the distal dying flap . Surg Forum 30:527, 1979 8. Kinmonth 18, Sheppard RC: Accidental injection ofthiopentone into arteries : Studies of pathology and treatment. Br Med J 2:914-9, 1959 9. Heggers JP, Loy GL, Robson MC , et al: Histological demonstration of prostaglandins and thromboxanes in burned tissue. J Surg Res 28:110-7, 1980

The Journal of HAND SURGERY

10. Heggers JP, Robson MC: In Ninnemann JL , editor: Traumatic injury , infect ion and other immunologic sequelae . Baltimore , 1983, University Park Press, pp 79-102 II. Van der Post CWH: Ca se of mistaken injection of pentothal sodium into an aberrant ulnar artery . South African M J 16:182, 1942 12. Cohen SM : Accidental intra-arterial injection of drugs . Lancet 2:409-16, 1948 13. Cohen SM: Accidental intra-arterial injection of drugs . Lancet 2:361-71 , 1948 14. Klabacha ME , Miller SH , Pav JM, et al: Inadvertent intra-radial arterial injection of cocaine . Ann Plast Surg 13:60-2, 1984 15. Ryan JJ, Hoopes IE, Jabaley ME: Drug injection injuries of the hands and forearms in addicts . Plast Reconstr Surg 53:445-51, 1974 16. Aibo D, Cheung L, Ruth L , et al: Effective intra-arterial injections of barbiturates . Am J Surg 130:676-8, 1970 17. Mancusi-Ungaro HR Jr, Decker WJ , Forshan VR , et al: Hand injury and parenteral abuse of propylhexebrine, Orthopedic Review 13:509-14, 1984 18. Hager DL, Wilson IN : Gangrene of the hand following intra-arterial injection. Arch Surg 94:86-9, 1967 19. Morgan NR , Waugh TR , Boback MD: Volkmann 's ischemic contracture after intra-arterial injection of cyclobarbital. JAMA 212:476-8 , 1970 20. Begg EJ, McGrath MA , Wade D: Inadvertent intra-arterial injection: A problem of drug abuse. Med J Aust 2:56 1-3, 1980 21. Lindell TD , Porter JM , Langston C: Intra-arterial injections of oral medications. N Engl J Med 287: 1132-3 , 1972 22 . Nathan P: Intra-arterial injection of barbiturate . Hand 7:175-8, 1975 23 . Petrie PW, Lamb DW: Severe hand problems in drug addicts following self-administered injections. Hand 5:130-4, 1973 24. Carey JP IV, Penn I: Cardiovascular complications of parenteral drug abuse . Contemporary Surgery 27:59-65, 1985 25 . MacIntosh RR, Hayward PSA : Intra-arterial injection of Pentothal. Lancet 2:571, 1943 26. Fell IN : Intra -arterial injection of tubocuraine and thiopentone. Br Med J 1:95-6 , 1953 27. Stone HH, Donnelly C: The accidental intra-arterial injection of thiopental. Anesthe siology 22:995-1006, 1961 28. Jelalian C , Mehrhof AI, Cohen KI, et al: Streptokinase in the treatment of acute arterial occlusion of the hand. J HAND SURG IOA:534-8 , 1985 29 . Kartchner M, Wilcox CW : Thrombolysis of palmar and digital arterial thrombosis by intra-arterial thrombolysin. J HAND SURG 1:67-74, 1976 30. Buckspan GS , Franklin JD , Novak GR , et al: Intra-arterial drug injury : Stud ies of etiology and potential treatment. J Surg Res 24:294- 301 ,1978

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31. Bum JH: Why thipentone injected into an artery may cause gangrene. Br Med 1 2:414-6, 1960 32. Bum IH, Hobbs R: Mechanism of arterial spasm following intra-arterial injection of thiopentone. Lancet I: 11125, 1959 33. Brown S, Lyons MS, Dunde lW : Intra-arterial barbiturates: A study of some factors leading to intravascular thrombosis. Br J Anaesth 40:13-9 , 1968

Thromboxan e in intra-arterial drug injections

34. Robson MC, Murphy RC, Heggers IP : A new explanation for the progressive tissue loss in electrical injuries. Plastic Reconstr Surg 73:431-7, 1984 35. Penneys NS: Inhibition of arachidonic acid oxidation in vitro by vehicle components. Acta Derm VenereoI62:5961, 1982

Arterial stump pressure: A determinant of arterial patency? Twenty-seven patients with acute injuries to the radial or ulnar arteries had arterial repairs using microvascular techniques. No patient had an ischemic hand secondary to his arterial injury. The overall patency rate for all repaired vessels was 56%. For sharp, clean lacerations, the success rate for repairs was 55%. Repairs of acute, sharp lacerations yielded no better results than delayed reconstructions. The average distal end arterial stump pressure for patent arteries was 66% of mean, while for thrombosed vessels it was 76% of mean; this was not a statistically significant difference (p = 0.9). There was no statistical correlation between forearm arterial patency, age, sex, vessel injured, mechanism of injury, time of repair, or clinically measured distal arterial stump pressure. At the present time, it does not appear to be possible to predict arterial patency by measuring arterial stump pressure at the time of definitive repair. (J HAND SURG 1987;12A:245-9.)

James A. Nunley, M.D. , Richard D. Goldner, M.D ., L. Andrew Koman, M.D. , Richard Gelberman, M.D ., and James R. Urbaniak, M.D. , Durham and Winston-Salem, N.C., and San Diego, Calif.

Forearm arterial lacerations continue to present a perplexing problem to the reconstructive sur-

From the Division of Orthopaed ic Surgery, Duke University Medical Center, Durham, N.C. , and Bowman Gray School of Medicine , Section of Orthopaedic Surgery, Winston-Salem, N.C., and the Division of Orthopaedics and Rehabilitat ion, University of California , San Diego Medical Center, San Diego, Calif . Received for publication April 3, 1986; accepted in revised form Aug. 6, 1986. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article . Reprint requests: James A. Nunley, M.D., Duke University Medical Center, P. O. Box 2919, Durham, NC 27710.

geon . Based on a review of patients with arterial injuries from World War II, the rate of amputation of the forearm after ligation of both radial and ulnar arteries was 39%, and the incidence of amputation of the hand after ligation of the radial artery alone was 5%.1.2 In 1967, Boswick' reported on a series of patients with repair of the radial and ulnar arteries in the forearm . Of his 65 patients with repaired forearm vessels, none of the repaired vessels was patent at follow-up . In 1982, we reported on 62 patients with 90 injuries to the radial or ulnar arteries." The overall success rate for all repairs was 54%. This represented a significant improvement in patency over the data of Boswick but stilI did not approach the arterial patency rates that we have demonstrated with smaller digital vessels . In 1982, we hypothesized that the arterial stump pressure when eleTHE JOURNAL OF HANDSURGERY

245