Intramuscular accident with drug injection in the deltoid muscle: local and distant lesions, review of 32 cases

Abstracts

Analysis of 32 cases of accidental injection of oily suspension (in most cases) into the deltoid muscle is reported. Pain and local ulcers characterized the accidents. In many cases, simultaneous ischemic disorders were observed in the scapular and pectoral regions and especially in the end of the upper limb. It is presumed that this complex lesion was caused by 1) the harmful action of the medication on nervous terminations, soft and perivascular tissues; and/or 2) occasional entrance of the substance into blood vessels, causing embolism and/or thrombotic endothelitis; and/or 3) vasomotor phenomena. Hand injuries were generally more severe than injuries in the deltoid region, with occasional spontaneous or surgical loss of fingers. Clinical statuses were similar, though some lesions had features, which allowed identification of peculiar physiopathogenic mechanisms, with conceptual and therapeutic significance.

Livedoid dermatitis; arteritis cutis medicamentosa; embolia cutis medicamentosa; Nicolau syndrome; Freudenthal syndrome; accidental intramuscular injection; gangrene of the hand

Análise de 32 casos de acidentes por injeção, na maioria das vezes, de substâncias oleosas no músculo deltoide. Os acidentes caracterizaram-se por dor e reações tróficas locais. Em muitos casos, simultaneamente, ocorreram distúrbios isquêmicos nas regiões escapular, peitoral e, especialmente, na extremidade do membro. Presume-se que esse complexo lesional é gerado: 1) pela ação lesiva do medicamento nas terminações nervosas, nos tecidos moles e perivasais; e/ou 2) pela entrada fortuita da substância no interior dos vasos, produzindo embolia e/ou endotelite trombosante; e/ou 3) pelo despertar de fenômenos vasomotores. As lesões da mão, geralmente, foram mais graves que as lesões deltoidianas, com a eventual perda de dedos, espontânea ou cirúrgica. Os diversos quadros clínicos do acidente foram semelhantes, mas algumas características lesionais permitiram identificar mecanismos fisiopatogênicos peculiares, o que tem significado conceitual e terapêutico.

Dermite livedoide; arterite cútis medicamentosa; embolia cútis medicamentosa; síndrome de Nicolau; síndrome de Freudenthal; acidente por injeção intramuscular; gangrena de mão

REVIEW ARTICLE

Intramuscular accident with drug injection in the deltoid muscle: local and distant lesions, review of 32 cases

Fernando Luis Vieira Duque^I; Carlos Alberto Araujo Chagas^II

^IMembro benemérito e fundador, SBACVRJ. Professor titular, Angiologia, Pontifícia Universidade Católica do Rio de Janeiro (PUCRJ), Rio de Janeiro, RJ, Brazil. Chefe, Serviço de Angiologia, Hospital Geral da Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Ex-professor, Angiologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil

^IIMembro , SBACVRJ. Angiologista, Serviço de Angiologia, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Mestre, UFRJ, Rio de Janeiro, RJ, Brazil. Professor, Morfologia, Universidade Federal Fluminense (UFF), Rio de Janeiro, RJ, Brazil. Professor, Anatomia, Universidade Gama Filho (UGF), Rio de Janeiro, RJ, Brazil

Correspondence

ABSTRACT

Analysis of 32 cases of accidental injection of oily suspension (in most cases) into the deltoid muscle is reported. Pain and local ulcers characterized the accidents. In many cases, simultaneous ischemic disorders were observed in the scapular and pectoral regions, especially in the ends of upper limbs. It is presumed that this complex lesion was caused by 1) the harmful action of the medication on nerve endings, soft and perivascular tissues; and/or 2) occasional entrance of the substance into blood vessels, causing embolism and/or thrombotic endothelitis; and/or 3) vasomotor phenomena. Hand injuries were generally more severe than injuries in the deltoid region, with occasional spontaneous or surgical loss of fingers. Clinical statuses were similar, though some lesions had features allowing identification of peculiar physiopathogenic mechanisms, with conceptual and therapeutic significance.

Keywords: Livedoid dermatitis, arteritis cutis medicamentosa, embolia cutis medicamentosa, Nicolau syndrome, Freudenthal syndrome, accidental intramuscular injection, gangrene of the hand.

Introduction

The advent of the hypodermic syringe in 1853 (Charles Gabriel Pravaz), soon followed by the manufacturing of all-glass syringes in 1869 (Georg Wilhelm Amathus Luer), enabled parenteral administration of medications. Already in 1893, Fournier¹ wrote that mercury injections caused in situ "des sphacéles de veritables gangrenes locales". According to Nicolau,², Welander³, in 1898, described the first case of skin necrosis caused by local injections. In 1906, Nicolsky⁴ described gluteal gangrene secondary to mercury injections and suggested the oily suspension embolic origin of the lesion. In 1924, this ischemic thromboembolism was described by Freudenthal⁵ in three cases of necrosis of the buttocks caused by intramuscular injection of bismogenol in the course of treatment for syphilis. Freudenthal^5,6 would later label the new entity "embolia cutis medicamentosa". One year later, Nicolau² described a similar clinical status, also involving oily injections to gluteal muscles, highlighting the discoloration found at the early stages of the trauma (livedoid dermatitis), as well as the subsequent gangrene. Nicolau drew a distinction between cases caused by oily embolism and cases of thrombotic arteritis caused by medications in aqueous suspensions. Later, other authors^7-9 noticed the existence of distinct clinical forms and proposed the disease be classified in one of two different types: Freudenthal's benign embolic exanthem and Nicolau's livedoid and gangrenous dermatitis. The classification did not stick, however, and since then the disease has received various different names, such as embolia cutis medicamentosa, Freudenthal syndrome, Nicolau syndrome, livedoid dermatitis, and Nicolau's dermatitis, among others. The labels have been used indiscriminately, applying to any accident on the site of a hypodermic injection with local caustic and/or allergic reactions. Similar cases were described in the early twentieth century, with some authors^10,11 categorizing them under distinct clinical statuses.

Though Nicolau's dermatitis is well known among Brazilian dermatology services,^12,13 it only reached Angiology services as the specialty arose during the mid-twentieth century. In 1947, Murgel and Regalla¹⁴ described a case of accidental intramuscular injection of benzathine penicillin into the deltoid muscle and assumed the skin lesions were secondary to embolism, but did not associate the clinical status to Nicolau syndrome. In 1948, we see the first report of this accident in the case of a young medical student who took oily bismuth injections to treat syphilis: at the moment the substance was injected into his deltoid muscle, he felt intense local pain, soon followed by paleness, numbness, and coldness in his hands. The hand disorders improved with anesthetic blockades of the cervical sympathetic stellate ganglion. Afterwards, however, the deltoid lesion became ulcerate, leaving a retractable scar, as well as causing necrosis and mummification of a finger (Figure 1). Microscopic examination of the skin from the deltoid region showed the presence of foreign material in the small arteries of the region, suggesting the material happened to enter the arterial tree, i.e., the embolic nature of the lesion. Based on findings from the local examination, we assume that the disorders of the hand had the same embolic origin. Simple radiography of the hand in this and three other cases showed small opaque spots in the fingers, similar to the cases reported by Murgel¹⁴, Gammel¹⁵ and Kimberley¹⁶. The finding was considered compatible with the presence of droplets of bismuth salt in the arteries. In experimental work on corpses done at the time,¹⁷ we found that the oily dye injected into the circumflex arteries of the humeral neck ran against the flow to the axillary artery, from which it then flowed to the arteries of the hand. Since they were performed on exsanguinated arteries, they do not allow us to confirm with absolute certainty the presence of this pathogenic mechanism in the lesions on these patients' hands. In 1952, six cases of this accident were reported during the First Congress of the Latin American Angiology Chapter, in Buenos Aires.¹⁷ In all cases, concurrently with the local injection, there were vascular and trophic disorders in the homolateral hand. At the time, there were very few reports of this type of accident happening to the deltoid region, and even fewer about the lesions to the hand and fingers with which they are associated. There were reports of similar cases in the gluteal region, with or without compromise of the sciatic nerve, but few referring to vascular conditions affecting the foot.^15,18 In the following years, more cases involving the upper limbs were reported in congresses,^19-21 but without making the etiopathogeny of the process evident. In 1967,²² surgical assessment of the presence of occlusive substances in the forearm arteries of a patient who had suffered a shoulder-hand lesion caused by the injection of procaine penicillin into the deltoid muscle was reported, confirming the hypothesis of embolism at the source of vascular and trophic disorders of the hand in at least some of these cases. The embolic and necrotizing effects of oily substances injected directly into the lumen of the artery were already known, having been found in clinical cases and proven experimentally, though the lesions had some degree of variability depending on the what substance was injected. In rabbit ears, phenilbutazone caused severe inflammation when injected into the lumen or around the artery, followed by necrosis.²³ A similar phenomenon was found in dogs.²⁴ The injection of benzathine penicillin with sodium dipyrone, responsible for one of these accidents, did not cause histological or arterial lesions when injected experimentally into the ears of rabbits.²³ However, the injection of benzathine penicillin or oily bismuth into the paws of dogs caused inflammatory lesions similar to those seen in clinical cases.^24,25

Embolia cutis medicamentosa is a rare and still little known entity. It is usually confused with similar, more frequent diseases, also secondary to intramuscular injection of medications. In Brazil, during the 1940s and 1950s, bismuth and mercury salt injections in oily suspension were a widespread treatment for syphilis. Injections were usually administered to the gluteal region, but sometimes to the deltoid muscle, where there is a greater chance they would enter a vessel. In the following years, injections of benzathine and procaine penicillin became the most important causes of the accident.²⁶ With the reduction of muscular administration of oily or crystalline medications, such events began to happen less and less; in recent years, the most commons aggressors have been products in aqueous suspensions, anti-influenza agents, and anti-inflammatories.

In the last few decades, several other identical accidents have been identified, also increasing the number of cases reported in medical publications and congresses.^27-44

Signs and symptoms

Most of the time, the accident is characterized by pain and histological reactions on the injection site, with immediate or delayed appearance. Sterile inflammation is slow to evolve, ultimately resulting in necrosis, ulceration and scarification with retractable fibrosis.

In some cases, the accident is more severe, characterized by intensive pain at the moment and site of the injection, closely followed by a local irritative reaction. Usually, the skin around the puncture site becomes discolored, similar to the paleness of a corpse; little by little, cyanotic patches begin to appear, alternating with pale patches to form a thick, irregular mesh of livedoid, marble aspect. Later, the patches darken; eventually, vesicles filled with bloody content begin to appear. Slowly, the cyanotic patches become darker from ischemic necrobiosis, and gangrene sets in with variable levels of extensiveness and depth. In almost every case, the deltoid region becomes swollen and edematous, with the eventual formation of an abscess. Two of our cases also suffered from histological lesions of the necrotizing fasciitis kind. Some cases also included fulminating superinfections, and gaseous or anaerobic gangrene, as reported by some authors.^{11,25,30,33,36,45,46}

Inflammatory lesions to local soft tissues are believed to derive from the caustic action of the product, its concentration, its volume and, more rarely, the mechanical action of the needle. The aggressive event in the nerve endings is of similar origin. This local lesion complex may be accompanied by an ischemic necrotizing component of greater or lower intensity and importance, generated by the compromise of vessels: lesions to the arteries, arterioles and veins would occur due to the accidental entrance of the substance into the vessel's lumen or caustic action on the adventitial, with secondary inflammation of the walls and occlusive thrombosis. The oily drug, upon penetrating the artery, generates emboli and occludes the lumen, while the drug in an aqueous suspension, upon reaching the arterial and/or venous lumen, harms the endothelium and causes secondary thrombosis. Lesions to somatic and/or perivascular nerve endings trigger sympathetic vasomotor reflexes, causing vascular constriction and worsening the ischemia and/or infarction of tissues irrigated by the relevant vessels.¹¹

According to reports, accidents occur with a wide range of medications, such as corticosteroids, penicillin, interferon alpha, metoclopramide, pyrazolones, anesthetics, noradrenaline, phenilbutazone, diclofenac, chemotherapeutic drugs, vitamins, and others.⁴⁷ The most often reported oily products are bismuth- and mercury-based, balsamic, and penicillin. Plastic methacrylate was responsible for one case of nasal necrosis after injection during a rhinoplasty.⁴⁸

To Fernet,¹¹ except in the case of tissue necrosis, there would be no embolic-thrombotic obstruction of local vessels: the vascular spasm, caused by the medication exciting the sympathetic innervation, would be the cause of benign forms of the accident. The multifactorial origin of the local lesion enabled Barthélemy¹⁰ to hypothesize the existence of four different types of livedoid dermatitis: 1) local embolic exanthem; 2) ecchymotic and phlyctenular patches; 3) livedoid and granular dermatitis; 4) deep hypodermic and muscular gangrene. He makes no reference to the lesions of the hand we observed afterwards.

Sometimes, the lesion to the deltoid is accompanied by ischemia in the extremities of the limb, possibly leading to necrosis of the fingers or even the hand and forearm. In almost all patients in this study, ischemic alterations of the hand regressed, but in some the lesion progressed to necrosis and mummification of the digital pulp or of the whole finger. Various authors report cases in which the hand or even the forearm had to be amputated.^{3,7,12,22,25,28,49-52}

Distal ischemic necrotizing disorders, accompanying the lesion to the shoulder, usually represent a greater problem than the lesion to the deltoid. Supposedly, the substance injected into the muscle happens to penetrate the circumflex arteries of the humeral neck, reaches the axillary artery, and from there moves to one of its branches, conditioned by the normal anatomic variations of the axillary arterial network.⁵³ This is one of the mechanisms that might explain the occurrence of lesions in the scapular, pectoral and, above all, hand regions. Similarly, we can assume that the entrance of materials into circumflex veins causes phlebitis and local infarction; eventually, part of the medication may flow centripetally and cause thrombophlebitis in deep venous trunks. In this type of accident, the oily product may even reach the lungs and cause pulmonary embolism.² Lesions restricted to the nerves are rare, responsible for clinical statuses dominated by sensitive manifestations with poor vascular components.

In almost all cases in this study, there were local or distal neural and vasomotor conditions secondary to stimuli from excitement of perivenous sympathetic nerves and/or mixed nervous in the deltoid region.²³ In some cases, arterio-arterial spasms are the most important pathogenic factor for the syndrome and the primary target of its treatment.

Poor motor and/or painful function of the limb has almost always been present, from the first moments of the accident. There were reports of fainting and dizziness at the time of the accident for four patients, without other systemic manifestations.

Diagnosing this iatrogenic morbid process of the deltoid and the ultimate distal compromise is relatively easy, based on anamnesis and physical examination. Assessing the presence and degree of vasomotor and occlusive phenomena of hand vessels can be done using clinical semiology, response to sympathetic blockade, and, especially, the induced reactive hyperemia test.⁵² Simple hand radiographs can reveal the presence of heavy metal microembolisms in the arteries.^16,18,21 The event would certainly be more clearly seen by modern imaging processes. In the cases in this study, microscopic examination of injured tissue was only done for scientific purposes, since biopsy is not required as a semiotechnical process for diagnosing the syndrome, especially because, in human patients and in experimental animals, histological testing performed at a later date failed to reveal the presence of anything but unspecific inflammatory processes.^{24,26,35-37,45,46,50,52-55} More sophisticated semiotechnical methods are recommended in cases of organic occlusion of arterial stems and surgical repair of occluded arteries.

Analysis of cases as a whole

The 32 cases in this study do not represent the incidence of intramuscular accidents with drug injection in the deltoid muscle for the population as a whole, since Hospital Geral da Santa Casa da Misericórdia do Rio de Janeiro does not provide services to underage patients, and its Angiology Service receives patients referred by other, non-specialized services. Similarly, this study did not take into consideration cases with incomplete examination and/or progression. Also, patients whose necrotizing lesions have already set in go directly to surgery services.

The small number of cases studied here prevents us from making statistical inferences, but it is sufficient for insight into individual clinical statuses; despite the monotonous similarity of shoulder lesions, and even lesions of the arm-hand complex, we can identify different etiopathogenic mechanisms, a fact of conceptual and therapeutic import. All patients are young adults; incidence did not differ in terms of sex.

Three patients experienced intensive pain at the moment of the injection, with local inflammatory reaction followed by necrosis of the skin (one case) and retractable scars (two cases). None suffered disorders of the hand and none improved with sympathetic blockades. Of all accidents secondary to intramuscular injections, this is the most frequent, both in the deltoid region and in the gluteal. The small number of cases of this type of lesion in our service may be explained by the fact that they are relatively benign and often treated at the accident sites themselves, precluding the need for specialized services. The lesion is likely derived from the irritating and/or allergic action of the medication on local soft tissues, especially the muscle and hypodermis (myositis and panniculitis cutis medicamentosa). As reported, it eventually becomes factitious panniculitis, with progression including the formation of nodules, loss of tissue, and cicatricial fibrous depression.

Two patients experienced intensive local pain which spread through the limb and neck. Initial local dystrophic manifestations were not severe, but they were followed by muscle and dermis atrophy on the next few days, including motor dysfunction of the deltoid. There was little skin dystrophy, and no edema or major vasomotor disorders of the limb. Anesthetic blockade of the cervical sympathetic nerve did not relieve the symptoms. Later, one patient presented sympathetic dystrophy reflexes in the injured limb.^20,56 The absence of vascular disorders in both cases allows us to assume that no circumflex vessel was affected, as well as that no upstream vasomotor stimuli were formed. The aqueous irritating substance would have affected only the nerve endings in the region, causing immediate intensive pain, as well as its propagation, followed by atrophy of the deltoid muscle (neuritis cutis medicamentosa). That would be the source of the stimulus triggering the anomalous sympathetic reflex arc. The two patients were left with serious impairment of limb movement.

After the deltoid injection of a substance in aqueous suspension, three patients had small local reaction with moderate pain. Soon after, the injection site became congestive and cyanotic. After a few hours (12 hours for one patient and the following morning for two others), the upper limb became edematous from the shoulder and scapula to the fingers. Limb motion was partially impaired and there was moderate diffuse pain, slightly bluish coloration throughout the limb, and turgescence of shallow veins (Figure 2). The injection site was swollen, with no sign of skin necrosis. There was no sympathetic blockade. The use of heparin and oral anticoagulants led to progressive improvement in clinical status. Weeks later, there was only discrete edema throughout the limb and, in two cases, mild dystrophy in the deltoid region. The hands and fingers were normal. We can assume that caustic medication entered the circumflex vein(s) and cause endothelial dysfunction and thrombosis with local infarction (phlebitis cutis medicamentosa). Similarly, it is possible that as the irritating substance flowed upstream, it reached the subclavian vein, there causing deep vein thrombophlebitis of the limb (phlebitis medicamentosa).

Six patients experienced intensive pain immediately after the injection of anti-inflammatories in aqueous suspension, followed by livedoid discoloration in the deltoid region, a finding similar to those reported by other authors. In five cases, local lesions progressed to necrosis and the breakdown of muscle and skin. Three patients had vasomotor disorders of the fingers and edema of the shoulder and scapular region, one of which regressed spontaneously and two of which responded to sympathetic anesthetic blockades. Two patients who only received treatment after some period of time did not respond to sympathetic blockades and developed necrosis of the fingers. This type of lesion may be a consequence of injecting irritating substances into the lumen of circumflex arteries, causing endothelial dysfunction, lesion to artery walls, secondary thrombosis, and ischemia and necrosis of downstream tissues (arteritis cutis medicamentosa).⁵⁷ Vascular disorders of the hand seem to derive from vasomotor reflexes generated at the level of product action and/or injection into the vessels of the hand, with the medication reaching the hand via the circumflex arteries of the humerus and arterial trunks of the limb (arteritis medicamentosa). In these cases, the irritating agent's dispersion through the bloodstream of the limb might explain why vascular disorders of the hand are infrequent.

In 18 patients, the medication injected (bismuth, mercury, anti-influenza agent, penicillin) was in an oily suspension. All experienced major local pain at the site of the injection, soon followed by numbness (nine cases) and numbness and pain in the hands and fingers (seven cases). Two patients experienced only minimal symptoms in their hands. Thirteen cases involved poor function. All patients had early onset of a livedoid aspect to the skin around the injection site, soon followed by erythema, swelling, ulceration, and vesicles followed by necrosis (Figure 3). Sixteen patients presented ischemia of the hand and/or forearm, with pain in their fingers, hypothermia, paleness and cyanosis of the skin. Two patients, examined at the time of the accident, had impalpable radial and ulnar pulses, but which normalized after cervical sympathetic blockades. Two patients experienced vasomotor and ischemic disorders of the pectoral region, while four experienced i in the scapular region. Vasomotor disorders of the hand responded well to anesthetic blockade of the sympathetic innervation, representing the primary treatment for almost all patients. Despite our best efforts, after some period of time, all patients presented necrotic lesions of the tissues in the deltoid region. Eight had necrotic fingertips (Figures 4 and 5) and six required surgical amputation of the phalanges of two or more fingers (Figure 6).

This type of accident seems to be caused by: 1) the accidental entrance of oily substances into the lumen of circumflex arteries, with arteriolo-arterial occlusion and upstream blockade of blood flow (embolia cutis medicamentosa)^4,5,17; and 2) the upstream flow of oily substances through circumflex arteries until they reach the axillary artery, running down scapular and thoracic branches, especially the arterial trunks of the extremity, and occluding distal vessels (embolic ischemia).¹⁷ Vasomotor phenomena of the arm and hand can have their origin in excitement of circumflex periarterial nerves or embolic arteritis of the fingers. Accidents of this type progress more severely than others, perhaps because they depend both on endotheliopathy caused by medications and on oily suspension thromboembolism. The prevalence of lesions of this type among our patients may be explained by the fact that patients were referred to the service due to the presence or severity of the lesions on their hands.

Overall, ischemia of the hand responded well to cervical-sympathetic neural blockades. In two cases, the response to anesthetic neural blockades was so striking as to enable us to infer the presence of vasomotor disorders as the primary agent for ischemia of the fingers, regardless of the presence of embolism in the arteries of the hand. Some authors⁵⁸ believe all lesions are secondary to the irritation of somatic and/or sympathetic perivascular nerves, unleashing a ganglionary vasomotor reflex, as hypothesized by João Cid dos Santos.⁵⁵

We do not believe we can accept the presence of a single etiopathogenic mechanism for the syndrome in our study. A global view of the cases reported thus far allows us to identify many signs and symptoms common to all, but also the fact that there are different clinical statuses (Figure 7). In some cases, a specific etiopathogenic factor stands out, but in most the manifestations seem to be determined by the participation, in different degrees, of the various pathogenic mechanisms involved in the process. Identifying the mechanisms involved in each case helps guide the choice of therapy.

Treatment

There is no specific treatment for lesions to the deltoid region or for ischemia of the hand. However, for most patients, the harmful consequences of the accident may be minimized. The therapeutic measures adopted in these cases vary depending on the presentation and progression of each case. Local pain was reduced through palliatives (skin anesthesia, cold, heat, etc.), without much success; in a few rare cases, featuring more intensive and/or persistent pain, local injection of anesthetic substances was required. The course of shoulder ulceration was accompanied by the usual local therapeutic care (bandages, antiseptics, anesthesia) and eventual surgical debridement. In a few cases, the local infection grew and required systemic antibiotics. Anticoagulants were administered to patients with thrombophlebitis and those with organic digital arterial occlusion who responded poorly to sympathetic nerve blocks. In no case were blockades done concurrently with the use of anticoagulants.

Even at low intensity, vascular compromise of the hand was treated using the Souza Pereira technique of anesthetic blockades of the cervical sympathetic chain, sometimes once or twice a day, during the first days of the disease. In some of the more resistant cases, the vasodilatator effect was heightened by the use of medications and heat at a distance. The ischemic necrotizing lesion of the fingers was handled routinely, always trying to save as much tissue as possible and waiting for the establishment of the limits of the necrosis before amputating the mummified phalanges. There were no cases of occlusion of arterial trunks of the forearm demanding disobstruction and/or reconstruction measures; likewise, no patient experienced gangrene of an entire hand or forearm, such as described by various authors.^26,46 Most patients were left with some locomotor disorder of the limb, which in almost every case diminished with physical therapy and/or time.

The lack of specific therapy for these iatropathogenic accidents is one of the elements behind the relative rarity of differential diagnosis of the syndrome and the catchall name of Nicolau syndrome for all abnormal reactions secondary to intramuscular injections.

It seems clear that the best treatment for these accidents is prophylaxis: avoiding the injection of caustic and/or oily substances into the deltoid muscle or using the appropriate site for administration, as well as all other basic recommendations found in nursing handbooks.

References

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Publication Dates

• Publication in this collection
  05 Jan 2010
• Date of issue
  Sept 2009

History

• Received
  25 Mar 2009
• Accepted
  06 July 2009