INTRA-ARTERIAL INJECTION OF DRUGS

REVIEW

Complications After Unintentional Intra-arterial Injection of Drugs: Risks, Outcomes, and Management Strategies
SURJYA SEN, MD; EDUARDO NUNES CHINI, MD, PHD; AND MICHAEL J. BROWN, MD
Unintentional intra-arterial injection of medication, either iatrogenic or self-administered, is a source of considerable morbidity. Normal vascular anatomical proximity, aberrant vasculature, procedurally difficult situations, and medical personnel error all contribute to unintentional cannulation of arteries in an attempt to achieve intravenous access. Delivery of certain medications via arterial access has led to clinically important sequelae, including paresthesias, severe pain, motor dysfunction, compartment syndrome, gangrene, and limb loss. We comprehensively review the current literature, highlighting available information on risk factors, symptoms, pathogenesis, sequelae, and management strategies for unintentional intra-arterial injection. We believe that all physicians and ancillary personnel who administer intravenous therapies should be aware of this serious problem.

Mayo Clin Proc. 2005;80(6):783-795

aPTT = activated partial thromboplastin time; IA = intra-arterial; IV = intravenous

ase reports and incidences of iatrogenic intra-arterial (IA) injection of medications have been published since the 1940s.1-3 Historically, medications most commonly associated with pronounced morbidity and mortality after unintentional IA administration were barbiturates and benzodiazepines.4-6 As might be expected, most of these medications were used for sedation or general anesthesia. Incidences of these unintentional IA cannulations and injections were reported to be as infrequent as 1 in 56,000 to as common as 1 in 3440.4,7 The resulting consequences led many early anesthesiologists and other medical practitioners to avoid or at least use lower concentrations of the commonly implicated agents (ie, sodium thiopental8). In spite of the use of dilute solutions, the consequences have still been devastating for many patients. When severe gangrene, limb ischemia, skin necrosis, and subsequent amputations have occurred, the vast majority of patients have had permanent disabilities. If no tissue loss has occurred, patients have still experienced long-term functional hand deficits, temperature hypersensitivity, and paresthesias. Lost productivity, prolonged rehabilitation, extended
From the Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minn. Individual reprints of this article are not available. Address correspondence to Eduardo Nunes Chini, MD, PhD, Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: chini.eduardo@mayo.edu). 2005 Mayo Foundation for Medical Education and Research

follow-up care, and extended periods of unemployment have contributed further to the list of consequences. Lastly, it should be noted that some comorbidities, especially psychiatric illnesses such as depression, persist long after the duration of symptoms and disabilities caused initially by IA injections. Years of therapy and rehabilitation may be needed to overcome some of these sequelae. One example case is that of a healthy 20-year-old college student who was referred to our institution for revascularization and skin grafting after 25 mg of intravenous (IV) promethazine was unintentionally infused into the radial artery of his left forearm. Upon injection, initial signs and symptoms (within 15-20 seconds) consisted of intense forearm pain and mottling of the skin on his hand. Minutes thereafter, discoloration and nail bed pallor became evident. Approximately 3 to 4 hours later, the symptoms had progressed to paresthesias and pronounced hand weakness. Rapid development of signs indicative of necrosis (by the eighth day) required the patient to undergo fasciotomies, multiple dbridements, and 4 skin grafts for cosmesis. Relatively little improvement in symptoms (cold sensitivity, nonhealing scratches, hand weakness, and generalized extremity pain) was noted at 6-month follow-up. Years of debilitation are now a possible outcome in what had been an anticipated routine and uneventful appendectomy in a young healthy patient. Moreover, lost time from school, work, and social interactions has contributed to the patients new-onset depression and inactive lifestyle. Examples of the extreme sequelae often experienced by patients with inadvertent IA injections are typified in this case. Figure 1 shows the patients left forearm during one of the wash-out procedures after the fasciotomies and preliminary skin grafts. Also, this case demonstrates the importance of educating health care practitioners about the implications of IA injections. Awareness of risk factors, associated signs and symptoms, and available therapeutic modalities is necessary for anyone involved in administering IV therapy. Such awareness can decrease the incidence, delays in diagnosis, and resulting complications of iatrogenic IA injections. During the past few decades, the source of the problem has shifted from primarily hospitalized patients to people who abuse IV drugs.9-14 The morbidity associated with these cases is similar, if not more severe. Additionally, the number of implicated medications has increased from a few sedatives to a much larger and diverse group of substances.
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INTRA-ARTERIAL INJECTION OF DRUGS

FIGURE 1. Left forearm of a healthy 20-year-old man after promethazine was unintentionally infused into his radial artery. Top and Bottom, Appearance during a washout procedure after fasciotomies and dbridement were performed for skin necrosis.

Because no standard treatment modalities have been established for unintentional IA injection, many therapeutic interventions have been attempted with varying degrees of success. In this review, we present the results of a MEDLINE/ PubMed search for the terms inadvertent, accidental, and intra-arterial injections. English language articles published between 1966 and the present that discussed or reported various substances that have been described as dangerous with IA injection were reviewed. Also, we list and discuss common symptoms, corresponding pathophysiology, histopathology, typical sequelae, and the various treatment and prevention modalities that have been attempted or recommended. SYMPTOMS AND RISK FACTORS With unintentional IA injection, both acute and chronic manifestations can be expected. Many patients complain of immediate discomfort (often within seconds), ranging from local irritation15-19 to intense pain distal to the site of injec784 Mayo Clin Proc.

tion.20-25 Soon thereafter, many patients will report sensory problems such as tingling, burning, and paresthesias. Altered motor function (involuntary muscle contractures and muscle weakness) and cutaneous manifestations (flushing, mottling) have been reported11,26-37 (Figure 2). Within 7 to 10 days, further evidence of vascular compromise may become evident. Pulselessness, pain, cyanosis, paresthesias, pallor, and paralysis may indicate the onset of compartment syndrome. Eventually, tissue necrosis, gangrene, and permanent functional deficits develop (Figure 2 and Table 1). In addition to disfigurement and functional deficits, sequelae may include the development of chronic pain and complex regional pain syndrome in the affected limb. Because pain is often the initial symptom, patients who cannot report discomfort are often subjected to an increased IA dose of medication. This may result in an increased likelihood of severe adverse sequelae. Such patients include those who are undergoing general anesthesia, receiving mechanical ventilation, comatose or have altered mental status, mentally handicapped, of the pediatric population, and trauma victims with distracting injuries. Other patients known to be at risk for unintentional IA injection include those who are morbidly obese and those with darkly pigmented skin, thoracic outlet syndrome (vanishing radial pulse with abduction/internal rotation of the arm), indwelling arterial catheters for blood pressure measurement, or preexisting vascular anomalies of the forearm.19,45,61,70 In all patients, clinicians must be aware of the physical examination findings associated with arterial injection and be cognizant of other indicators suggestive of IA cannulation. As reported by Ghouri et al,45 these indications include the following: bright red backflow of blood into an IV catheter, presence of pulsatile movement of blood in the IV tubing, backflow of blood into the IV tubing even with fluid bag at a level higher than catheter insertion site, high-risk anatomical locations where arteries and veins are close (such as in the antecubital fossa), and increase in blood pressure reading with an indwelling arterial catheter when an ipsilateral IV is bloused with fluid. However, these indicators are often equivocal or subtle at best. If IA placement is suspected, confirmatory testing should be performed with either blood gas analysis or pressure transduction. Another particularly high-risk group of patients involves those in a critical care setting. Many have an arterial catheter inserted for continuous blood pressure monitoring. These patients are often intubated, sedated, and receiving mechanical ventilation, and they require multiple infusions through several IV lines with numerous ports. In a setting in which a medication needs to be administered urgently or emergently, it is easy to envision how a medication could be injected through a port of an arterial line. In a discussion
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INTRA-ARTERIAL INJECTION OF DRUGS

Acute Initial injection 30 min-2 h Within 24 h 24-36 h Within 48 h Within 1 wk

Chronic 10-14 d

Pain on injection Flushing Numbness Weakness

Skin mottling Cramping Phlebitis Paresthesias Motor deficit

Symptoms of compartment syndrome

Necrosis Gangrene Autoamputation

Nail bed pallor Decreased capillary refill

Muscle swelling Digital edema Ischemic contractures Functional hand deficits

Permanent contractures Clinical and laboratory evidence of rhabdomyolysis

FIGURE 2. Spectrum of symptoms, ranging from acute to chronic, associated with unintentional intra-arterial injection of drugs.

of such a case, Jones61 outlined a protocol for the maintenance of an arterial catheter while keeping the risk of IA injection to a minimum: using clear labeling and colorcoding lines and extension sets; using only cannulas and tubing without injection ports for arterial pressure transduction; keeping a port, if it is necessary, close to the insertion site of the cannula; tracing each extension line to the site of the cannula before injecting medications; and educating all health care professionals who are involved in administering medications of the risks, symptoms, and complications of unintentional IA injections. A preexisting vascular anomaly is a risk factor commonly overlooked by health care professionals. Most cases of unintentional IA cannulation involve radial artery branches of the forearm and hand. Gonzalez-Compta74 reported that the most common arterial anomaly of the upper limb is a high-rising (origin above the intercondylar line) radial artery resulting in a superficial branch (Figure 3, left). The prevalence of this particular vascular anomaly is between 1% and 14%.76,77 This anomaly typically results in the radial artery ending in a thin superficial palmar branch that stops in the thenar region or, at best, completes a scant palmar arch with the ulnar artery. As with the superficial branch that passes ventral to the flexor retinaculum, this palmar branch may also be inadvertently cannulated in an attempt to gain IV access. Another common anomaly of the radial artery is termed the antebrachialis superficialis dorsalis (Figure 3,
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right). This involves a radial artery bifurcation in the forearm, resulting in an anomalous superficial branch that ends as an incomplete palmar arch between the index finger and thumb; the prevalence of this anomaly is 1%.78 Often, this branch of the radial artery will cross underneath a terminal branch of the cephalic vein, just superficial to the radial styloid processa common site for insertion of IV catheters (often referred to as the intern vein). Although most cases of unintentional arterial cannulation involve the radial artery branches of the forearm and hand, superficial ulnar arteries have been reported in 2.26%41 to 3.1%79 of patients, and 12 variations of the superficial arch and 7 variations of the deep palmar arch have been described.80 The antecubital fossa and groin are also sites for potential errors. The brachial artery can be cannulated rather than the median basilic vein26 simply because of the proximity of the 2 vessels. Since a similar relationship exists between the femoral artery and vein, it is not surprising that cases of unintentional cannulation of the femoral artery (in an attempt to gain IV access into the femoral vein) have been published.65,81-84 PATHOPHYSIOLOGY Although the clinical syndrome of IA injections is well defined, the underlying pathophysiologic mechanism remains unclear. Many mechanisms have been proposed and
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TABLE 1. Drugs Associated With Severe Complications After IA Injection* Medication Benzodiazepines Diazepam15-19 Midazolam38 Temazepam (case series of 9 patients)39 Sequelae Phlebitis, vascular impairment No initial symptoms, later symptoms resolved without sequelae Histological: myocyte necrosis, interstitial edema, arterial and venous thrombosis, vasculitis, endothelial denudation Clinical: compartment syndrome, rhabdomyolysis, gangrene Forced wrist flexion, pulselessness, decreased sensation Gangrene Gangrene Gangrene Chemical endarteritis, immediate vasoconstriction, thrombosis, tissue necrosis, endothelial cell destruction (on histological analysis), tissue necrosis Necrosis Gangrene Blanching, pain, forced wrist flexion, cyanosis, edema Gangrene Gangrene Gangrene Ischemic injury, digital necrosis Gangrene Digital gangrene Paraplegia from thromboembolism to spinal artery54; gangrene55 Paresthesias, cramping, gangrene Necrosis Signs of malperfusion on presentation,56 severe ischemia57 Gangrene Gangrene Ischemic contractures, functional hand deficits60 Cyanosis, digital artery occlusion, gangrene, death Gangrene Thrombosis Vasospasm, ischemia Edema, erythema, pain resolved with only minimal bruising Gangrene Gangrene Marked ischemic appearance Immediate pain, flushing, progression to gangrene Gangrene Gangrene Amputation None necessary Fasciotomies, amputations Interventions

Chlordiazepoxide26 Phenothiazines Promethazine40,41 Chlorpromazine42 Promazine32,41,43,44 Barbiturates Thiopental3,21-25,27-34,37,45-47

IA papaverine injection, full recovery Sympathetic block, heparinization NR NR Procaine injection into artery, stellate ganglion block, early anticoagulant therapy (heparin), papaverine, phenoxybenzamine, IA urokinase, IA reserpine, tolazoline Methimazole, aspirin, aloe vera, methylprednisolone NR Amputations, 6; full recovery, 12 NR NR NR Digital amputation NR Lidocaine, stellate ganglion block, amputation, skin grafting Amputation55 NR NR Hyperbaric oxygen therapy, axillary plexus catheter block (ropivacaine)56; full recovery56,57 NR NR Amputation,60 continuous axillary plexus block59 Papaverine, stellate ganglion block NR NR Axillary block, IV dextran, IA tolazoline, salicylate anticoagulation, elevation, compression IV lidocaine, stellate ganglion block Amputation NR Caudal injection (10 mL of 0.25% bupivacaine); full recovery Local anesthetic, papaverine, sympathetic block NR NR

Thiopental (rabbit ear model)48 Quinalbarbitone11,12,28 Secobarbital12,36 (18 cases) Pentobarbital29 Amobarbital28,41 Amphetamines Propylhexedrine49 Levoamphetamine11,32,50 Methylphenidate51 Antibiotics Flucloxacillin52,53 Penicillin54,55 Narcotics Microcrystalline cellulose25 Heroin6 Levomethadone56,57 Meperidine41 Propoxyphene58 Cocaine59,60 Miscellaneous Phenytoin61,62 Sulfobromophthalein32 (phenolphthalein used to test hepatic function) Parenteral nutrition63 Phentaramine (oral anorexiant)9 Sodium bicarbonate64 IA dextrose solution Tubocurarine33 Atracurium65 Hydroxyzine66 Pentazocine6,67,68 Methohexital69
59

*It is well known that IV injection of propofol can result in symptoms of immediate discomfort, burning, and pain, similar to the initial presenting symptoms with IA injections. This poses the difficulty of discerning whether a catheter is IA when a patient first reports these symptoms. Fortunately, multiple authors70-73 evaluating both human and animal cases have corroborated that IA injection of propofol has no sequelae. Of course, the negative aspect is that, if the catheter has inadvertently been placed IA, the clinician will not easily be able to discern this based on the symptoms associated with propofol injection. IA = intra-arterial; IV = intravenous; NR = not reported. IV abuse of crushed tabletsmethadone, oxycodone, acetaminophen, aspirin with codeine, propoxyphene, and phenobarbital. In a rabbit ear model, IA injection of meperidine was noted to be harmless.66

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are discussed subsequently. All proposed mechanisms result in tissue ischemia distal to the injection site. NOREPINEPHRINE-MEDIATED VASOCONSTRICTION THEORY Burn and Hobbs46 reported that vasoconstriction occurred after IA injection of thiopental into the ear of a rabbit. They hypothesized that the vasoconstriction was mediated by norepinephrine. The authors pretreated rabbits with cocaine (to increase the effect of catecholamines), tolazoline (used for -adrenergic blockade), and reserpine (used for depleting central and peripheral catecholamines) before IA injection of thiopental. Vasoconstriction distal to the site of injection was increased, abolished or reversed, and slight or absent, respectively. However, the observed vasoconstriction was often followed by resumption of normal arterial flow and sometimes vasodilation (also corroborated by Kinmonth and Shepherd85). Hence, it was concluded that noradrenaline played a part in (acute vasospasm) but was not entirely responsible for the pathogenic process. THROMBOSIS THEORY Kinmonth and Shepherd85 reported that heparinization was beneficial against the formation of gangrene in the aforementioned rabbit model. They hypothesized that arterial thrombosis must play some role in the pathogenesis, particularly in the long-term sequelae seen after IA injection of thiopental. Brown et al28 reported that red blood cell hemolysis occurred after IA injection of thiopental, and they hypothesized that the subsequent release of adenosine diphosphate could initiate platelet adhesion and aggregation. To test this theory further, they conducted a separate in vitro study in which thiopental was added to platelet-rich plasma. A precipitous decrease in platelet concentration, measured at 0, 5, and 10 minutes after mixing, was noted, suggesting thrombus formation. Arquilla et al26 reported that the arterial catheter, in addition to the medication injected though it, may play a role in the incidence of arterial thrombosis. Catheter-related factors that could potentially increase the incidence of thrombosis after arterial injection are as follows: duration, catheters left in place more than 48 hours; size, larger catheters correlate with increased thrombus formation; shape, tapered catheters; and material, non-Teflon catheters. Crystal Theory As early as 1966, Waters8 proposed that distal perfusion could be blocked when a drug precipitates out of a solution. In studies done on rabbit legs and cadaveric human extremities, Waters8 proposed that the crystals of thiopental occlude flow when they become jammed in the lumen of the arterial system. After occlusion, a compensatory reMayo Clin Proc.

FIGURE 3. Left, Superficial palmar arch forms from a high-rising radial artery. The open arrow shows the normal branching point, and the solid arrow shows the abnormal variant. Because of this aberrant high bifurcation, the branch is fairly superficial in the forearm where unintentional cannulation may occur easily.75 Right, Anomaly of the antebrachialis superficialis dorsalis radial artery. This variance runs superficially past the radial styloid processa site commonly used for cannulation of one of the terminal branches of the cephalic vein (often referred to as the intern vein).75 In both left and right, the black outlines show typical venous patterns, illustrating how these abnormal arteries course in proximity to commonly cannulated veins.

lease of noradrenaline was thought to occur. Thrombosis and gangrene often followed. Waters8 postulated that the crystal theory could explain both the early and the longterm sequelae that occur after IA injection. Jones61 reported that many medications are soluble at pH values more alkaline than the pH level of arterial blood and theorized that these substances crystallize rapidly after IA injection. This theory was corroborated by Brown et al28 who observed similar crystal formation when they mixed thiopental and methohexital into whole blood. As these crystals wash downstream, they not only mechanically obstruct distal flow but also can initiate chemical endoarteritis. Of note, although solutions of an alkaline pH were initially thought
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to contribute to the pathogenesis by causing vasospasm, both Burn and Hobbs46 and Kinmonth and Shepherd85 provided contrary evidence. Injection of thiopental was noted to cause arterial vasoconstriction, but injection of equal volumes of other isotonic control solutions with the same pH as thiopental produced no evidence of arterial vasospasm. ENDOTHELIAL INFLAMMATION THEORY Initially described by Cohen4 in 1948 and subsequently corroborated by Kinmonth and Shepherd,85 Engler et al,32 Maxwell et al,81 and Ryan et al,86 the endothelial inflammation theory is based on inflammatory changes in the endothelium, subendothelium, and muscle layers due to chemical endoarteritis. Using 9 case studies of IA injections of temazepam, Dodd et al39 further categorized the histological changes associated with endothelial cell injury. They noted profound interstitial edema, arterial and venous thrombosis, and variable degrees of myocyte necrosis. Interstitial edema and vascular thrombosis typically led to compartment syndrome, resulting in considerable morbidity. DIRECT CYTOTOXICITY THEORY In 1991, MacPherson et al21 described thiopental-induced direct arterial endothelial destruction. In an effort to elucidate the pathogenesis on a molecular level, they conducted in vitro studies of rabbit ear artery segments. They noted that 2.5% thiopental caused denuding of the vascular endothelium in as quickly as 2 minutes. Thereafter, when the segment of blood vessel was tested for reactivity to vascular constrictors and dilators, the authors noted that the effects of exogenous constrictors and dilators (noradrenaline and glyceryl trinitrate, respectively) were unchanged, suggesting that the vascular smooth muscle function was unaffected. However, when the arterial segments were perfused with acetylcholine to induce the release of dilators such as the endothelium-derived relaxing factor, minimal effect was noted. Thus, the authors postulated that IA injection of substances such as thiopental causes denuding of the endothelium by a direct cytotoxic effect. This then led to ischemia caused by a spasm (or more appropriately, a lack of dilation) that occurred when dilators such as endothelium-derived relaxing factor were reduced significantly or absent. The authors pointed out that, from a treatment standpoint, any strategy that used endothelium-dependent vasodilation to enhance flow in thiopental-affected arteries would be less effective than methods that were not dependent on an intact and functional arterial endothelium. VENOUS CONSTRICTION THEORY Ellertson et al87 reported angiographic evidence of both arterial and venous irregularities after IA injection of 10%
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thiopental into arteries of rabbit ears. After 72 hours, they noticed that segmental areas of venous thromboses were more prominent than those seen in the arterial system. Furthermore, dye extravasation into edematous tissues was more evident in the tissues surrounding the venous system. After 3 weeks, they noticed that the gangrenous areas were in close correlation with the extravasated contrast medium. The authors concluded that venospasm and thrombosis lead to outflow obstruction, which in turn causes transudation, edema, cyanosis, and eventually arterial stasis with resulting ischemic necrosis. LIPID SOLUBILITY THEORY Knill and Evans6 noted similarities among different medications that result in ischemia and gangrene after IA injection. Most of the implicated medications were highly lipid soluble. In a rabbit ear model,6 diazepam (highly lipid soluble) was compared to ketamine (relatively hydrophilic) with normal saline injections as a control group. The authors found that the ears injected with diazepam became gangrenous (Figure 4), whereas those injected with ketamine did not (injection of ketamine was equivalent to injection of normal saline). Routine pathologic studies of the diazepam group consistently showed necrosis and gangrene. The sequence of events leading to gangrene in the diazepam group is shown in Figure 4, with the corresponding histological changes shown in Figure 5. HIGH OSMOLARITY THEORY Evans et al64 suggested that the osmolarity of a solution may be implicated in the severe tissue damage that occurs after IA injection. They described a patient who experienced pain, edema, and erythema after unintentional IA injection of sodium bicarbonate. In addition to the high pH of the solution, the authors thought that the high tonicity of the injected solution (approximately 2000 mOsm/L) could have played a role in the resulting tissue damage. Perhaps Brown et al28 stated it best: The multiplicity of explanations for the damage resulting from intra-arterial [injections] suggests that there exists a lack of basic knowledge of the fundamental mechanisms involved. Nonetheless, a few concrete conclusions can be drawn from the work done by various investigators who have attempted to discover and explain the pathogenesis. 1. Not all medications will cause ischemia via the same exact mechanisms. For instance, some may cause crystallization, whereas others may be directly toxic to the endothelium. 2. Regardless of the various mechanisms implicated, thrombosis seems to be the common end point for all IA pathogenesis.
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3. Understanding the pathogenesis is essential to developing appropriate treatment modalities, especially since large prospective human studies are not feasible. TREATMENT Because of the incomplete understanding of the underlying pathophysiology and the impracticality of performing casecontrolled, prospective human studies, specific treatment algorithms have not been well developed. Most interventions are largely empirical, aiming to maintain perfusion distal to the site of injury. No prospective human studies have shown that any specific treatment is superior to another. An overwhelming number of instances in the literature have been case reports consisting of only 1 or 2 patient encounters. Studies performed with animal models have directly refuted interventions reported as successful in humans. Furthermore, the large majority of patients in whom IA injections occur are IV drug abusers. This patient population does not often seek immediate medical care, and delays in presentation often preclude clinicians from maximizing therapeutic interventions. Regardless of the extent of injury and types of interventions, management of these cases should center on the following 5 main clinical end points: (1) symptomatic relief, (2) cessation or reversal of arterial spasm, (3) maintaining and/or reestablishing blood flow to the distal portions of the extremity, (4) treating any sequelae of vascular injury and ischemia (edema, compartment syndrome, infection, necrosis, and gangrene) that may occur, and (5) rehabilitation. On the basis of these clinical end points, the following management approach is proposed. STEP 1: IF IATROGENIC, MAINTAIN THE IA CATHETER When an inadvertent IA injection is suspected, the first instinct may be to remove the indwelling catheter. However, from a practical standpoint, this is not the best approach. First, the catheter can be used for diagnostic purposes by transducing the intravascular pressure or drawing a sample for blood gas analysis. Second, maintaining the IA catheter will allow immediate delivery of multiple medications to the site of injury. Third, if the patient needs to be evaluated by angiography, the IA catheter will facilitate the injection of contrast dye directly into the implicated vasculature. If the catheter can still be flushed and there is no blood clot, the initial step is to start a slow infusion of an isotonic solution (such as 0.9% saline solution) to maintain catheter patency. Although empirical, this recommendation follows the logic of using the catheter to maintain access to the surgical tissues and vasculature. Of note, currently, no data are available regarding outcomes after this intervention. Hence, further experiments need to be performed to determine its effectiveness.
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Period of obvious vasoconstriction

Within a few minutes to half an hour

Ear becoming dusky and cool

Over next 48 h

Gradual development of edema

Over course of 1 wk

Area of necrosis appears and spreads

10 d after injection

FIGURE 4. Top, Rabbit ear 14 days after injection of diazepam. From Can Anaesth Soc J,6 with permission. Bottom, Timeline of changes seen in rabbit ear model after injection of diazepam.6

STEP 2: IDENTIFY THE PROGRESS OF THE DISEASE Depending on the given history, delay in presentation, physical examination findings, perfusion studies (such as Doppler ultrasonography, angiography, compartment pressures), and any implicated comorbidities (diabetes mellitus, atherosclerosis, vasculitides, hypercoagulable states, etc), the clinician can identify the acuteness or chronicity of the problem. Certain clinical indicators can be roughly correlated with disease progression (Figure 2). Although it does not directly affect therapy, assessing disease progress can be useful in gauging prognosis and in helping the clinician set realistic expectations of recovery for the patient. In the largest study of its kind, Treiman et al88 developed a Tissue Ischemia Score based on signs and symptoms at presentation of 48 patients with IA drug injections. Patients were assigned either a 0 or a 1 (for the absence or
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Vasodilation and vascular congestion

Within a few minutes to half an hour

Vessels seen as structurally normal

Over next 48 h

Extravasation of red blood cells and inflammatory response

Over course of 1 wk

Thrombi in arteries and necrotic changes apparent

10 d after injection

FIGURE 5. Histological changes on microscopic sections seen after injection of diazepam.20

Furthermore, the amount of gangrene was even less when treatment with heparin was extended from 2 days to 4 days. However, significant mortality was also noted in the test group, in which several animals died due to hemorrhage. Gaspar and Hare12 proposed a regimen of IV heparin injections every 6 hours for the first 24 hours, followed by intramuscular injections for the next 5 days (although they did not specify a target range of aPTTs that could be considered as therapeutic). Arquilla et al26 recommended that every patient in whom IA injection is suspected undergo angiography and pretreatment with a heparin bolus (as long as no contraindications exist). Furthermore, they pointed out that heparin may help with arterial spasm and that some patients may even improve with only this therapy. Anticoagulation may present a problem if the unintentional IA injection is noticed postoperatively (as the patient wakes up and reports the symptoms). However, in patients in whom risk of bleeding is minimal, even though no consensus guidelines exist for maintaining certain aPTT values as markers for therapeutic levels, treatment with heparin is usually advocated. STEP 4: INSTITUTE SYMPTOMATIC RELIEF AND PLAN REHABILITATION Regardless of the extent of disease progression, providing symptomatic relief should be a priority. Increased sympathetic vascular tone (from high pain states), edema distal to the site of injury, and muscle injury or forced flexion contractures can all be treated initially with noninvasive interventions. Obtaining consultation from pain management, physical medicine/rehabilitation, and massage therapy services may be helpful. Multiple case reports suggest that simple interventions consisting of analgesia, elevation, massage, and initiation of therapy with passive motion devices were all critical for treatment and recovery. Elevation of Extremity. Elevating the extremity15,25,45 is a simple intervention that can be used to decrease edema and reduce compartment pressures. However, there is a possibility that elevating the extremity may be detrimental if perfusion is already decreased. In general, elevation should help to decrease interstitial edema without compromising arterial blood flow. Massage. Ghouri et al45 described a case of IA injection of thiopental (350 mg) that initially resulted in 2+ edema and cyanotic changes. The case was managed with only elevation of the affected extremity and regular massage during the course of 3 days; symptoms resolved completely. Local Anesthetic Infiltration and Extremity Sympatholysis. For information regarding these 2 modalities, see the section entitled Step 6.
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presence) for 4 symptoms: cyanosis, cool extremity, delayed capillary refill, and sensory deficit. Of patients who had a Tissue Ischemia Score of 2 or lower, 92% had a normal outcome. Of patients who had a score greater than 2, only 41% had a normal extremity; the remainder had tissue necrosis or permanent neurologic dysfunction. Hence, identifying the progress of disease can help the clinician correlate the presenting signs and symptoms with an expected prognosis. STEP 3: INITIATE ANTICOAGULATION Barring any contraindications, anticoagulation with heparin seems to be broadly accepted as the initial intervention in the treatment of IA injections. Furthermore, because it is generally agreed that thrombosis is a key pathogenic step common to most IA injections, anticoagulation should be seriously considered early in treatment. Currently, no consensus exists on initial bolus amounts, appropriate target ranges for activated partial thromboplastin times (aPTT), or duration of therapy. However, similar to guidelines for treatment of pulmonary emboli,89 an initial loading dose of heparin of 60 IU/kg, followed by adjustment to maintain a mean aPTT level that is 1.5 to 2.3 times higher than normal, is recommended. The duration of therapy can be guided by resolution of symptoms, angiographic evidence of clot resolution, or need for surgical intervention. Heparin anticoagulation was first evaluated by Kinmonth and Shepherd85 using a rabbit ear model. Aiming for clotting times of at least twice the normal, they showed a statistically significant decrease in the area of necrosis.
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STEP 5: WHEN INDICATED, TREAT WITH ANTIBIOTICS Because of the risk of infection (especially in those who abuse IV drugs), many clinicians may believe it is necessary to empirically provide coverage against gram-positive organisms and anaerobes. However, in the study by Treiman et al88 of 48 patients who were IV drug abusers with IA injections, antibiotics were withheld unless obvious signs of infection were present. Of the patients in whom antibiotics were withheld, none showed any cellulitic changes, wet gangrene, or evidence of spreading infection. In contrast, Cooper et al90 stated that coverage against clostridial infections is of paramount importance in the aforementioned patient population. Administration of antibiotics, however, is not without associated risks and morbidities. A logical approach when considering antibiotic administration in this patient population is to monitor for signs of infection and initiate therapy accordingly. If infection is suspected, attempts should be made to identify the causative organism with blood cultures. Of note, IV antibiotics may have poor penetration into necrotic tissue, often making it difficult to assess effectiveness of therapy. STEP 6: PERFORM SPECIFIC INTERVENTIONS After implementing the first 5 steps, the clinician must determine what specific intervention would benefit the patient most. A review of the literature during the past 60 years yields multiple options, none of which have been proved to be consistently effective or evaluated on a large scale. Furthermore, interventions range from noninvasive to procedures requiring specialist-driven care and close monitoring. These various modalities are described subsequently in detail. Local Anesthetic Injection. Therapeutic IA injections of a local anesthetic, such as procaine and lidocaine, have often been performed to prevent reflex vasospasm.91,92 Sadat-Ali et al92 reasoned that lidocaine can induce vasodilation and that IA injection of lidocaine could have therapeutic value. Twelve hours after inadvertent IA injection of thiopental, 2 boluses of 10 mL (0.5% lidocaine without epinephrine) of lidocaine were injected. The authors reported clinical and angiographic evidence of reperfusion within minutes. The efficacy of arterial local anesthetic injection (0.25 mL of 4% procaine) was originally tested in the rabbit ear model by Kinmonth and Shepherd,85 and they found that vasospasm was prevented for a maximum of 10 minutes. Conducting the experiments for a period of a few weeks showed no difference in the amount of tissue loss between the treated and untreated groups. As pointed out by Ghouri et al,45 the procedure is associated with a risk of damaging the artery and thereby compromising the blood supply to the already affected limb.
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The possibility of central nervous system and cardiac toxicity with administration of local anesthetics must always be considered. Intra-arterial dosages of lidocaine (without epinephrine) should not exceed 2 mg/kg in a single dose and 4.5 mg/kg for a total dose. This maximum safe intravascular dose of lidocaine should not be confused with the maximum dose of lidocaine often documented for use in peripheral nerve blockade, 7 mg/kg. The latter takes into account the addition of epinephrine to provide vasoconstriction and delayed systemic absorption. Extremity Sympatholysis. Stellate ganglion blocks may be performed to decrease or prevent reflex vasospasm and prolonged vasoconstriction.40,45,52 This intervention fits well with the therapeutic goals of relieving pain, maintaining perfusion, and decreasing vasospasm; however, because of the associated risks, it may not be a first-line intervention in some patient populations. Patients who are obese, have chronic obstructive pulmonary disease, or have indications of only minimal vascular compromise may benefit from less invasive modalities. Of note, in some reported cases,10,90 stellate ganglion blocks did not improve eventual outcome. Multiple authors9,56,59 have reported success with axillary plexus blocks, especially since this technique allows use of a continuous catheter. Berger et al59 reported a favorable clinical outcome when an unintentional IA injection of cocaine was treated with an axillary brachial plexus block (40 mL of 1% lidocaine, then continuous infusion of 0.5% bupivacaine for 48 hours). Pain relief and return of normal color, warmth, and pulse were noted within 30 minutes. Adjunctive therapy of heparin (for 48 hours) and aspirin (for 6 days) was also used. Kessell and Barker65 reported similar success; lower extremity sympatholysis was achieved by using a caudal block after injection of atracurium into the femoral artery of a child. Extremity sympatholysis was also tested by Kinmonth and Shepherd85 in the rabbit ear model. Although not readily applicable in clinical situations, surgical sympathectomy showed a higher statistically significant decrease in the amount of gangrene. The mean area of tissue loss was 8.8 cm2 in the treated group vs 14.5 cm2 in the untreated group. It is important to consider the implications of performing an invasive procedure such as a nerve block on patients who are undergoing anticoagulation. This decision should be made before initiation of heparin, and the clinician must weigh the pros and cons of each form of therapy before deciding to use one or another or a modified combination of both (such as maintaining aPTT values lower than twice the normal and performing a single injection block instead of inserting a continuous infusion catheter).
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Arterial Vasodilators. Calcium channel blockers,93,94 reserpine, and tolazoline20 have been tested with varying results. In 1990, Crawford and Terranova20 assessed the efficacy of treating IA thiopental injections with reserpine and tolazoline in rabbit ear models. After evaluation of reserpine and tolazoline separately and as combination therapy, no significant difference was seen in the amount of tissue necrosis between treated and untreated animals. In a case report by Boudaoud et al,94 IA injection of nicardipine was used to successfully treat acute ischemia of the lower limb after unintentional IA injection of the coloring agent Bonney blue. Because initial therapy with 1% lidocaine, corticosteroids, heparin, and an epidural infusion of bupivacaine was unsuccessful, the authors initiated an infusion of IA nicardipine. Beginning with 2 g kg1 min1, increasing the rate to 20 g kg1 min1 for a total of 4 hours, and then decreasing to 2 g kg1 min1, nicardipine was infused for a total of 24 hours. Clinical parameters and blood gas analysis of the limb showed improvement that was not seen with the initial therapy. The authors hypothesized that nicardipine was efficacious because it allowed calcium-mediated vasodilation of the vasospastic arteries. This vasospasm was originally thought to be due to release of calcium from hemolyzed red blood cells after IA injection of Bonney blue solution (which contains 96% ethanol). Thromboxane Inhibitors. Thromboxane, an inflammatory mediator that promotes vasoconstriction and platelet aggregation, has been implicated in the pathogenesis of vasospasm from IA drug injections. Zachary et al48 used the rabbit ear model to evaluate topical aloe vera and methimazole (specific thromboxane inhibitors). Using immunohistochemical staining to detect levels of thromboxane, they found almost complete blockade of production in the treatment groups. Furthermore, they noted that the percentage of ear survival was greater in the treatment groups, especially when aloe vera and methimazole were used in combination.48 Of note, aspirin, methylprednisolone, and methimazole all inhibited tissue thromboxane levels (each was tested individually), but none showed statistically significant decreases in tissue necrosis compared with controls. Iloprost. Iloprost (a prostacyclin analogue) has been used for various ischemic conditions, including atherosclerotic disease, thromboangiitis obliterans, Raynaud syndrome, and ischemic leg ulcers, for its vasodilatory and platelet inhibiting properties. Case reports of its use in the management of IA injections have also been published.9,95-97 Samuel et al96 reported substantial improvement (in 4 hours) in a case of IA injection of heroin in which an IV infusion of iloprost (2 ng kg1 min1) was used in combination with heparin. Andreev et al97 reported a case of similar successfull recovery of function with iloprost (2 ng kg1 min1) as part of the treatment regimeneven
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when initial therapy with heparin, corticosteroids, analgesics, and thrombolytics (streptokinase, 100,000 IU/h) provided only temporary resolution of symptoms. IA Papaverine. Arquilla et al26 reported a case of IA injection of chlordiazepoxide into the brachial artery and subsequent signs and symptoms of pain, forced flexion of wrist, cyanotic skin, pulselessness, decreased sensation, and minimal capillary refill within 15 minutes. The patient was given heparin (10,000 U bolus) and analgesics. After angiography confirmed complete loss of blood flow to ulnar and radial arteries, the patient was given a bolus of IA papaverine (30 mg). Papaverine is an opium alkaloid that facilitates vascular smooth muscle relaxation by increasing intracellular cyclic adenosine monotriphosphate levels. The initial bolus was followed by an infusion of 180 mg over 10 hours. Full recovery of motor and sensory function was reported within 5 days with no surgical intervention. In 2002, Bittner et al14 reported a case of inadvertent IA injection of suspended tablets into the brachial artery that was successfully treated with papaverine (40 mg IV, 3 times, 4 hours apart). Of note, this treatment regimen was also combined with heparin, axillary plexus block (bupivacaine 0.25%, 10 mL/h), and urokinase (250,000 IU bolus, followed by continuous infusion over 12 hours). Failures of IA papaverine have also been reported. Jones61 used 15 mg of IA papaverine (combined with a 12hour stellate ganglion block) after unintentional IA injection of phenytoin; this regimen failed to prevent formation of ischemia and gangrene. Selective IA Injection of Thrombolytics. In 1989, Vangerven et al24 reported a case in which IA injection of 2.5% thiopental was treated with urokinase to achieve successful restoration of blood flow (determined by angiography). Initial symptoms included edema, cyanosis, decreased mobility, and severe pain. Blood flow was reestablished with thrombolytic therapy (urokinase, 75,000 IU bolus given 26 hours after the inciting event), and the patient was discharged 5 days later with only residual swelling. At 2week follow-up, no problems were reported. Three years after Vangerven et al24 reported their success with urokinase, Angel et al22 published a study that evaluated urokinase for treatment of injuries associated with thiopental injection in a rabbit ear model. In a prospective study involving 4 groups (10 in each group), the rabbits were evaluated for necrosis 2 weeks after an injection of only thiopental (group 1), thiopental followed by normal saline (group 2), thiopental followed by urokinase (group 3), and only normal saline (group 4). The extent of necrosis in each group was reported as a percentage: group 1, 21.2%; group 2, 17.5%; group 3, 46.5%; and group 4, 0%. The results of this study imply not only that urokinase is without benefit but also that it may actually exacerbate the damage
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INTRA-ARTERIAL INJECTION OF DRUGS

caused by IA thiopental injections. As the authors pointed out, it is difficult to ascertain the clinical implications of this animal model; however, until the mechanisms are better defined, use of urokinase should not be encouraged. Tissue plasminogen activator has been reported as successful treatment for IA injection. Pratikto et al98 described a case of a 21-year-old woman who injected 3 dissolved flunitrazepam tablets into the ulnar artery and was successfully treated with prostaglandin E1 and recombinant tissue plasminogen activator. Hyperbaric Oxygen Therapy. In a case described by Adir et al,57 hyperbaric oxygen therapy was initiated 12 days after a patient presented because of IA injection of methadone and flunitrazepam. The initial therapeutic regimen of systemic vasodilators, low-molecular-weight dextran, and aspirin was unsuccessful. However, hyperbaric oxygen therapy resulted in near-complete resolution of ischemic signs and symptoms. Because hyperbaric oxygen is noninvasive and adverse effects are minimal, this form of treatment is an option to consider in any patient. Corticosteroids. Corticosteroids have been a mainstay of treatment of many conditions involving inflammation. Thus, many authors have reported the use of corticosteroids as part of therapeutic regimens for the inflammatory reactions involved with IA injectionsboth with and without success.48,66,97 However, the use of corticosteroids as the sole therapy has not been evaluated in humans. Both IA and intramuscular dexamethasone after hydroxyzine injection were evaluated in the rabbit ear model by Enloe et al.66 A significant decrease in symptoms and full recovery were noted with both methods of administration (the IA form provided better results than the intramuscular form). Of note, Taweepoke and Frame99 reported a case of unintentional IA injection of Depo-Medrone (a depot form of methylprednisolone available in the United Kingdom). Depo-Medrone was given in conjunction with lidocaine for the attempted treatment of tenosynovitis stenosans. However, when the medication was accidentally injected into the radial artery, acute ischemia resulted. This complication required management with IV heparin, IA streptokinase, and surgical thrombectomy. Although not mentioned by the authors, it is possible that additives in the depot form (and not the corticosteroid itself) may have been responsible for the resulting ischemia. Of note, the vast majority of available treatment options are based on anecdotal and animal-model evaluations. Nonetheless, a basic treatment algorithm can be designed on the basis of the available literature. The 5 clinical end points of symptomatic relief, arterial spasm management, reestablishment of blood flow, treatment of sequelae, and long-term rehabilitation can be used to guide most therapy (Figure 6).
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Suspected intra-arterial injection

Iatrogenic

Noniatrogenic

Maintain intra-arterial catheter

Obtain baseline angiogram

Initiate infusion of 0.9% saline solution* via arterial catheter to maintain patency

Assess for signs and symptoms of infection (culture if necessary)

Confirm diagnosis

Initiate antibiotic therapy as needed

If no contraindications, initiate anticoagulation via venous catheter

Provide symptomatic relief Nonsteroidal anti-inflammatory drugs and opioids for pain control Elevation of extremity to reduce lymphedema Massage therapy Axillary nerve blockade as indicated Manage arterial spasm Calcium channel blockers Heparinization vs extremity sympatholysis (see text for details) Antispasmodics (ie, papaverine) Injection of local anesthetics Thromboxane inhibitors Iloprost (vasodilator and platelet aggregation inhibitor) Reestablish blood flow Thrombolytics Surgical thrombectomy Treat sequelae Necrotic tissue dbridement Antibiotic therapy as indicated Set up long-term rehabilitation Physical/occupational therapy Chronic pain management

FIGURE 6. Algorithm for treating unintentional intra-arterial injection of drugs. *At rate of 1 mL kg1 h1. By blood gas analysis, angiography, or pressure transduction.

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CONCLUSION A literature search for inadvertent IA injection of medications yields hundreds of articles discussing various case reports, animal models, physiochemical hypotheses, and implicated anatomical variations. However, because of the logistic difficulties in obtaining a large sample size of patients and collecting a consistent body of prospective data on this topic, no appropriate therapeutic guidelines have been formed. Furthermore, the true incidence rates, natural history, and pathophysiologic factors surrounding these complications are unclear. From a preventive standpoint, the best tools available to health care practitioners are assessment of risk factors, vigilance, knowledge of the typical medications that should not be used for IA injection, and an appreciation of the devastating consequences associated with inadvertent IA injection of drugs. From a treatment standpoint, the best options are immediate recognition of the situation, assessment of disease progress, pain control, anticoagulation, rehabilitation, and specific therapy.

REFERENCES 1. Lundy JS. Clinical Anaesthesia. Philadelphia, Pa: WB Saunders Co; 1942:542. 2. Van der Post CH. Report of a case of mistaken injection of pentothal sodium into an aberrant ulnar artery. S Afr Med J. 1942;16:182. 3. Macintosh RR, Heyworth PA. Intra-arterial injection of pentothal. Lancet. 1943;2:571. 4. Cohen SM. Accidental intra-arterial injection of drugs. Lancet. 1948; 255:409-417. 5. McLean CR, Cheng KS, Clifton MA. Fatal case of accidental intraarterial phenytoin injection. Eur J Vasc Endovasc Surg. 2002;23:378-379. 6. Knill RL, Evans D. Pathogenesis of gangrene following intra-arterial injection of drugs: a new hypothesis. Can Anaesth Soc J. 1975;22:637-646. 7. Dundee JW. Thiopental and other barbiturates. Int Anesthesiol Clin. 1956:197-243. 8. Waters DJ. Intra-arterial thiopental: a physico-chemical phenomenon. Anaesthesia. 1966;21:347-356. 9. Hamer R, Phelps D. Inadvertent intra-arterial injection of phentaramine: a complication of drug abuse. Ann Emerg Med. 1981;10:148-150. 10. Bhabra MS, Meshikhes AN, Thomson GJ, Craig P, Parrott NR. Intraarterial temazepam: an important cause of limb ischaemia in intravenous drug abusers. Eur J Vasc Surg. 1994;8:240-242. 11. Hawkins LG, Lischer CG, Sweeney M. The main line accidental intraarterial drug injection. Clin Orthop. 1973;94:268-274. 12. Gaspar MR, Hare RR. Gangrene due to intra-arterial injection of drugs by drug addicts. Surgery. 1972;72:573-577. 13. Charney MA, Stern PJ. Digital ischemia in clandestine intravenous drug users. J Hand Surg [Am]. 1991;16:308-310. 14. Bittner CH, Zuber M, Eisner L. Acute ischemia of the hand in a drug addict after accidental intra-arterial injection [in German]. Swiss Surg. 2002;8: 281-284. 15. Gould JD, Lingam S. Hazards of intra-arterial diazepam. BMJ. 1977; 2:298-299. 16. Doppman JL, Albertson K, Ramsey R, Saltzstein SL. Intra-arterial valium: its safety and effectiveness. Radiology. 1973;106:335-338. 17. Klatte EC, Brooks AL, Rhamy RK. Toxicity of intra-arterial barbiturates and tranquilizing drugs. Radiology. 1969;92:700-704. 18. Schulenburg CE, Robbs JV, Rubin J. Intra-arterial diazepam: a report of 2 cases. S Afr Med J. 1985;68:891-892. 19. Schneider S, Mace JW. Loss of limb following intravenous diazepam. Pediatrics. 1974;53:112-114.

20. Crawford CR, Terranova WA. The role of intraarterial vasodilators in the treatment of inadvertent intraarterial injection injuries. Ann Plast Surg. 1990;25:279-282. 21. MacPherson RD, McLeod LJ, Grove AJ. Intra-arterial thiopentone is directly toxic to vascular endothelium. Br J Anaesth. 1991;67:546-552. 22. Angel MF, Amiss EC, Amiss LR, Morgan RF. Deleterious effect of urokinase used to treat experimental intra-arterial thiopental injection injuries. Ann Plast Surg. 1992;28:281-283. 23. Lazarus HM, Hutto W, Ellertson DG. Therapeutic prevention of ischemia following intraarterial barbiturate injection. J Surg Res. 1977;22:46-53. 24. Vangerven M, Delrue G, Brugman E, Cosaert P. A new therapeutic approach to accidental intra-arterial injection of thiopentone. Br J Anaesth. 1989;62:98-100. 25. Goldberg I, Bahar A, Yosipovitch Z. Gangrene of the upper extremity following intra-arterial injection of drugs: a case report and review of the literature. Clin Orthop. 1984;188:223-229. 26. Arquilla B, Gupta R, Gernshiemer J, Fischer M. Acute arterial spasm in an extremity caused by inadvertent intra-arterial injection successfully treated in the emergency department. J Emerg Med. 2000;19:139-143. 27. Baillie TW. Accidental intra-arterial administration of thiopentone on the back of the hand. Br J Anaesth. 1958;30:373-374. 28. Brown SS, Lyons SM, Dundee JW. Intra-arterial barbiturates: a study of some factors leading to intravascular thrombosis. Br J Anaesth. 1968;40:13-19. 29. Burn JH. Why thiopental injected into an artery may cause gangrene. BMJ. 1960;2:414-416. 30. Culbert TD. Intra-arterial thiopental injection. BMJ. 1954;1:393. 31. Dundee JW. Intra-arterial injection of thiopental. BMJ. 1953;1:402. 32. Engler HS, Freeman RA, Kanavage CB, Ogden LL, Moretz WH. Production of gangrenous extremities by intra-arterial injections. Am Surg. 1964;30:602-607. 33. Fell JN. Intra-arterial injection of tubocuraine and thiopental. BMJ. 1953;1:95-96. 34. Forrester AC, Saunders RC. Intra-arterial thiopentone. Br J Anaesth. 1955;27:594-596. 35. King H, Hawtof DB. Accidental intra-arterial injection of ether. JAMA. 1963;184:241-242. 36. Morgan NR, Waugh TR, Boback MD. Volkmanns ischemic contracture after intra-arterial injection of secobarbitol. JAMA. 1970;212:476-478. 37. Rollason WN. Intra-arterial injection of thiopental-curare mixture. BMJ. 1950;1:1350-1351. 38. Sivalingam P. Inadvertent cannulation of an aberrant radial artery and intra-arterial injection of midazolam [letter]. Anaesth Intensive Care. 1999;27:424-425. 39. Dodd TJ, Scott RN, Woodburn KR, Going JJ. Limb ischaemia after intra-arterial injection of Temazepam gel: histology of nine cases. J Clin Pathol. 1994;47:512-514. 40. Promethazine [product information]. Available at: www.micromedex.com. Accessibility verified May 11, 2005. 41. Hager DL, Wilson JN. Gangrene of the hand following intra-arterial injection. Arch Surg. 1967;94:86-89. 42. Hodges RJ. Gangrene of forearm after intra-muscular chlorpromazine. BMJ. 1959;2:918-919. 43. Opinsky M, Serbin AF, Rosenfeld JE. Arterial thrombosis with gangrene after use of promazine (sparine) hydrochloride. JAMA. 1958;168:1224-1225. 44. Shell JH Jr, McIntyre DB Jr, Castellano J. Gangrene after use of gammadimethylamino-N-propyl phenothiazine hydrochloride (promazine): a case report. Am J Obstet Gynecol. 1959;78:1219-1220. 45. Ghouri AF, Mading W, Prabaker K. Accidental intraarterial drug injections via intravascular catheters placed on the dorsum of the hand. Anesth Analg. 2002;95:487-491. 46. Burn JH, Hobbs R. Mechanism of arterial spasm following intra-arterial injection of thiopentone. Lancet. 1959;1:1112-1115. 47. Mazumder JK, Metcalf IR, Holland AJ. Inadvertent intra-arterial injection of thiopentone. Can Anaesth Soc J. 1980;27:395-398. 48. Zachary LS, Smith DJ Jr, Heggers JP, et al. The role of thromboxane in experimental inadvertent intra-arterial drug injections. J Hand Surg [Am]. 1987;12:240-245. 49. Covey DC, Nossaman BD, Albright JA. Ischemic injury of the hand from intra-arterial propylhexedrine injection. J Hand Surg [Am]. 1988;13:5861. 50. Birkhahn HJ, Heifetz M. Accidental intra-arterial injection of amphetamine: an unusual hazard of drug addiction: case report. Br J Anaesth. 1973; 45:761-763.

794

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INTRA-ARTERIAL INJECTION OF DRUGS

51. Begg EJ, McGrath MA, Wade DN. Inadvertent intra-arterial injection: a problem of drug abuse. Med J Aust. 1980;2:561-563. 52. Zideman DA, Morgan M. Inadvertent intra-arterial injection of flucloxacillin. Anaesthesia. 1981;36:296-298. 53. McGrath P. Accidental intra-arterial flucloxacillin: management using guanethidine. Anaesth Intensive Care. 1992;20:517-518. 54. Stafford WW, Mena H, Piskun WS, Weir MR. Transverse myelitis from intraarterial penicillin. Neurosurgery. 1984;15:552-556. 55. Ozel A, Yavuz H, Erkul I. Gangrene after penicillin injection (a case report). Turk J Pediatr. 1995;37:67-71. 56. Ebert FW. Axillary plexus catheter block in accidental intra-arterial levomethadone HCl injection in an HIV-positive, hepatitis B and C active drug dependent patient [in German]. Handchir Mikrochir Plast Chir. 2000;32:197201. 57. Adir Y, Halpern P, Nachum Z, Bitterman H. Hyperbaric oxygen therapy for ischaemia of the hand due to intra-arterial injection of methadone and flunitrazepam. Eur J Vasc Surg. 1991;5:677-679. 58. Pearlman HS, Wollowick BS, Alvarez EV. Intra-arterial injection of propoxyphene into brachial artery. JAMA. 1970;214:2055-2057. 59. Berger JL, Nimier M, Desmonts JM. Continuous axillary plexus block in the treatment of accidental intraarterial injection of cocaine [letter]. N Engl J Med. 1988;318:930. 60. Klabacha ME, Miller SH, Pav JM, Demuth RJ. Inadvertent intraradial arterial injection of cocaine. Ann Plast Surg. 1984;13:60-62. 61. Jones NC. Inadvertent intra-arterial injection of drugs: why does it still occur? Br J Intensive Care. 1995;5:166-168. 62. Sintenie JB, Tuinebreijer WE, Kreis RW, Breederveld RS. Digital gangrene after accidental intra-arterial injection of phenytoin (epanutin). Eur J Surg. 1992;158:315-316. 63. Lynch JC, Shehabi Y. Stroke caused by inadvertent intra-arterial parenteral nutrition. Anaesth Intensive Care. 1995;23:358-360. 64. Evans JM, Latto IP, Ng WS. Accidental intra-arterial injection of drugs: a hazard of arterial cannulation: 3 case reports. Br J Anaesth. 1974;46:463-466. 65. Kessell G, Barker I. Leg ischaemia in an infant following accidental intra-arterial administration of atracurium treated with caudal anaesthesia. Anaesthesia. 1996;51:1154-1156. 66. Enloe G, Sylvester M, Morris LE. Hazards of intra-arterial injection of hydroxyzine. Can Anaesth Soc J. 1969;16:425-428. 67. Lindell TD, Porter JM, Langston C. Intra-arterial injection of oral medications: a complication of drug addiction. N Engl J Med. 1972;287:1132-1133. 68. Lloyd WK, Porter JM, Lindell TD, Rosch J, Dotter CT. Accidental intraarterial injection in drug abuse. Am J Roentgenol Radium Ther Nucl Med. 1973;117:892-895. 69. Francis JG. Intra-arterial methohexitone: injection into the central artery of the rabbits ear. Anaesthesia. 1964;19:501-506. 70. Ohana E, Sheiner E, Gurman GM. Accidental intra-arterial injection of propofol. Eur J Anaesthesiol. 1999;16:569-570. 71. MacPherson RD, Rasiah RL, McLeod LJ. Intraarterial propofol is not directly toxic to vascular endothelium. Anesthesiology. 1992;76:967-971. 72. Holley HS, Cuthrell L. Intraarterial injection of propofol. Anesthesiology. 1990;73:183-184. 73. Chong M, Davis TP. Accidental intra-arterial injection of propofol [letter]. Anaesthesia. 1987;42:781. 74. Gonzalez-Compta X. Origin of the radial artery from the axillary artery and associated hand vascular anomalies. J Hand Surg [Am]. 1991;16:293-296. 75. Bergman RA, Afifi AK, Miyauchi R. Arteries of the upper limb. Virtual Hosp [serial online]. Available at: www.vh.org/adult/provider/anatomy /AnatomicVariants/Cardiovascular/Directory/Region/ArteriesUpperLimb.html. Accessibility verified February 16, 2005.

76. Wood SJ, Abrahams PH, Sanudo JR, Ferreira BJ. Bilateral superficial radial artery at the wrist associated with a radial origin of a unilateral median artery [letter]. J Anat. 1996;189(pt 3):691-693. 77. McCormack LJ, Cauldwell EW, Anson BJ. Brachial and antebrachial arterial patterns: a study of 750 extremities. Surg Gynecol Obstet. 1953;96:4354. 78. Brown MJ, Edstrom LE, Zienowicz RJ. A symptomatic radial artery anomaly and its surgical treatment. J Hand Surg [Am]. 1999;24:178-181. 79. Hazlett JW. Superficial ulnar artery with reference to accidental intraarterial injection. CMAJ. 1949;61:289-293. 80. Kaplan EB, Spinner M. Kaplans Functional and Surgical Anatomy of the Hand. 3rd ed. Philadelphia, Pa: Lippincott; 1984. 81. Maxwell TM, Olcott C IV, Blaisdell FW. Vascular complications of drug abuse. Arch Surg. 1972;105:875-882. 82. Engler HS, Purvis JG, Kanavage CB, Ogden LL, Freeman RA, Moretz WH. Gangrenous extremities resulting from intra-arterial injections. Arch Surg. 1967;94:644-651. 83. Stonebridge PA, Callam MJ, Farouk M, Murie JA. Intra-arterial injection of oral medication in HIV positive drug addicts. Br J Surg. 1990;77:333-334. 84. Schanzer H, Gribetz I, Jacobson JH II. Accidental intra-arterial injection of penicillin G: a preventable catastrophe. JAMA. 1979;242:1289-1290. 85. Kinmonth JB, Shepherd RC. Accidental injection of thiopentone into arteries: studies of pathology and treatment. BMJ. 1959;2:914-918. 86. Ryan JJ, Hoopes JE, Jabaley ME. Drug injection injuries of the hands and forearms in addicts. Plast Reconstr Surg. 1974;53:445-451. 87. Ellertson DG, Lazarus HM, Auerbach R. Patterns of acute vascular injury after intra-arterial barbiturate injection. Am J Surg. 1973;126:813-817. 88. Treiman GS, Yellin AE, Weaver FA, Barlow WE, Treiman RL, Gaspar MR. An effective treatment protocol for intraarterial drug injection. J Vasc Surg. 1990;12:456-465. 89. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119(1, suppl):176S-193S. 90. Cooper JC, Griffiths AB, Jones RB, Raftery AT. Accidental intra-arterial injection in drug addicts. Eur J Vasc Surg. 1992;6:430-433. 91. Tin LN, Elalaoui MY, Akula E. Arterial spasm after administration of diazepam [letter]. Br J Anaesth. 1994;72:139. 92. Sadat-Ali M, Chowdhary UM, Mohanna M, Brismar J. Drug-induced arterial spasm relieved by lidocaine: case report. Acta Chir Scand. 1986;152: 697-699. 93. Ali AT, Montgomery WD, Santamore WP, Spence PA. Preventing gastroepiploic artery spasm: papaverine vs calcium channel blockade. J Surg Res. 1997;71:41-48. 94. Boudaoud S, Jacob L, Lagneau F, Payen D, Servant JM, Eurin B. Successful treatment of vasospastic acute ischaemia with intra-arterial nicardipine. Eur J Anaesthesiol. 1993;10:133-134. 95. de Koning YW, Plaisier PW, Tan IL, Lotgering FK. Critical limb ischemia after accidental subcutaneous infusion of sulprostone. Eur J Obstet Gynecol Reprod Biol. 1995;61:171-173. 96. Samuel I, Bishop CC, Jamieson CW. Accidental intra-arterial drug injection successfully treated with iloprost. Eur J Vasc Surg. 1993;7:93-94. 97. Andreev A, Kavrakov T, Petkov D, Penkov P. Severe acute hand ischemia following an accidental intraarterial drug injection, successfully treated with thrombolysis and intraarterial iloprost infusion: case report. Angiology. 1995;46:963-967. 98. Pratikto TH, Strubel G, Biro F, Kroger K. Intra-arterial injection of dissolved flunitrazepam tablets. Vasa. 2004;33:52-54. 99. Taweepoke P, Frame JD. Acute ischaemia of the hand following accidental radial artery infusion of Depo-Medrone. J Hand Surg [Br]. 1990;15: 118-120.

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