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Accidental intraartrial injection of diacethylmorphine (Heroin) in drug addicts - Three case reports
Abstract
Accidental intrarterial injections are not uncommon in medical treatments. This is also true for uncontrolled injections by drug-addicts. Since 2002 a number of 600 heavy opiate addicts in Germany are substituted in a country-wide study with pure diacetylmorphine (Heroine). We report the course and outcome of three cases of accidental intraarterial injections of pure diacetylmorphine under controlled conditions. After initial symptoms of vasospasms, all cases were without symptoms within one hour and no obvious loss of tissue was observed. After discussing the literature about medical literature and treatment options in intraarterial injections it is concluded, that the cause of major complications after intraarterial injections may not be the pure diacetylmorphine but additional substances in impure "street-heroin" samples.
... Three disease case reports presented by Passie et al. 21 showed that following intra-arterial injection of pure diacetylmorphine among three substance abusers, vasospasm symptoms were observed. In these cases, the patients recovered without any sequelae. ...
A AB BS ST TR RA AC CT T O Ob bj je ec ct ti iv ve e: : We aimed to evaluate the histopathological changes of intra-arterial midazolam injection on the arterial wall in a rat model and the effectiveness of increasing doses of lidocaine, a local anaesthetic, and papaverin, a peripheric vasodilator, on midazolam-induced arterial damage. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : In 72 adult Wistar albino rats, a linear abdominal incision was performed under anesthesia and, midazolam with or without 1.5 mg or 3 mg lidocaine or papaverine was injected under the branching area of the renal artery. The abdominal aorta section, which was distal to the injected area, was resected 1, 15 and 30 min after injection. The study consisted of a control group, which received no injection, and five main study groups and 11 subgroups, which differed by lidocaine and papaverine doses and time of evaluation. Samples were evaluated under transmission electron microscopy. Endothelial damage, interstitial oedema, lamellar damage, and neutrophil/lymphocyte infiltration were scored from 0 (non-damaged) to 4 (severe damage). R Re es su ul lt ts s: : Midazolam induced damage in arterial wall that was greatest at 30 min post-injection. Damage was less severe in the papaverin-injected group than lidocaine-injected subjects. The endothelial damage, lamella damage and interstitial oedema were less severe at the high lidocaine dose (3 mg) than low lidocaine dose (1.5 mg). C Co on nc cl lu us si io on n: : Midazolam injection into artery induces endothelial damage, lamella damage, interstitial oedema and neutrophil infiltration that were increased with time. Blood vessel wall damage caused by intra-arterial injection of midazolam can be prevented by papaverine or lidocaine in early stages. Therefore intra-arterial injection of midazolam should be treated promptly for long-term application of drugs. K Ke ey y W Wo or rd ds s: : Midazolam; papaverine; lidocaine; injections, intra-arterial Ö ÖZ ZE ET T A Am ma aç ç: : Çalışmamızın amacı midazolamın intraarteriyel enjeksiyon hasarını tespit etmek ve bir lokal anestezik ilaç olan lidokain ve vazodilatatör etkili papaverinin tedaviye erken yanıtta et-kilerinin doz artışına yanıtı ile birlikte incelenmesidir. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Toplam 72 yetişkin Wistar albino sıçanında, genel anestezi altında abdominal insizyon gerçekleştirildi ve 1.5 mg ya da 3 mg lidokain veya papaverin varlığında ya da yokluğunda midazolam renal arter dallanma alanının altında enjekte edildi. Enjeksiyon alanının distalindeki abdominal aorta enjeksiyondan 1, 15 ve 30 dak sonra çıkarıldı. Çalışma, enjeksiyon uygulanmayan kontrol grubu ve lidokain ve papaverin dozu ve değerlendirme zamanına göre değişen 5 ana ve 11 alt gruptan oluşuyordu. Örnekler trans-mision elektron mikroskobu ile değerlendirildi. Endotelyal hasar, interstisiyel ödem, lamellar hasar ve nötrofil/lenfosit infiltrasyonu 0 (hasarsız) ve 4 (ileri hasar) arasında skorlandı. B Bu ul lg gu ul la ar r: : Mida-zolam arteriyel duvarda enjeksiyon sonrası en fazla 30. dakikada olmak üzere hasar oluşturdu. Hasar papaverin uygulanan grupta lidokain grubuna göre daha azdı. Endotelyal hasar, interstisiyel ödem, lamellar hasar yüksek lidokain dozunda (3 mg), düşük lidokain dozuna (1,5 mg) göre daha azdı. S So on nu uç ç: : Midazolamın artere enjeksiyonu zaman içinde artan endotelyal hasar, interstisiyel ödem, lamellar hasar ve nötrofil infiltrasyonu oluşturur. Damar duvarındaki hasar erken evrede papave-rin ya da lidokain uygulanması ile azaltılabilir. Bu nedenle intraarteriyel midazolam enjeksiyonu sırasında bu ilaçlarla tedaviye acil olarak başlanmalı ve uzun süre devam edilmelidir. A An na ah ht ta ar r K Ke el li im me el le er r: : Midazolam; papaverin; lidokain; intraarteryel enjeksiyonlar T Tu ur rk ki iy ye e K Kl li in ni ik kl le er ri i J J A An ne es st t R Re ea an ni im m 2 20 01 13 3; ;1 11 1((3 3)): :1 10 09 9-2 20 0
... Often the outcome is disastrous with the loss of parts of the limb [6,13]. Only a few cases have been published concerning the lower limb [4,5,14,15], which often describe an adverse outcome, especially when diazepam was injected. Contrary to those cases found in the literature, our case presents a residue-free cure. ...
Objective: To ascertain the changes seen in vessel walls due to the intra-arterial morphine, fentanyl, dexmedetomidine and midazolam injections. Methods: 78 adult Wistar albino rats weighing approximately 250-300 grams were used. Six of the rats were controls. The other 72 were divided into four groups each containing 18 rats and each group was further divided into three subgroups of six animals each. In Group 1,100 μg kg-1 dexmedetomidine; in Group 2, 5 mg kg-1 morphine; in Group 3, 0.2 mg kg-1 fentanyl and in Group 4, 5 mg kg-1 midazolam were injected into the abdominal aorta from the distal area of the renal branch. A total of 18 specimens were taken from each group after 1, 5 and 30 minutes of injection. Histopathologic changes were examined with routine electron microscopy. Results: In the midazolam, fentanyl and dexmedetomidine groups, increased interstitial edema and neutrophile infiltration were found over time (p<0.05). However; there were no significant changes in the morphine group over time. A statistically important difference was found at the 1st, 5th and 30th minutes with respect to interstisial edema between the groups and at 30th minutes with respect to neutrphil infiltration. Conclusion: Dexmedetomidine, morphine, fentanyl and midazolam cause edema in the early period (1st minute), while infitration and histopathologic changes occur in 5th and 30th minutes.
Segmentation of 3D images of granular materials obtained by microtomography is not an easy task. Because of the conditions of acquisition and the nature of the media, the available images are not exploitable without a reliable method of extraction of the grains. The high connectivity in the medium, the disparity of the object's shape and the presence of image imperfections make classical segmentation methods (using image gradient and watershed constrained by markers) extremely difficult to perform efficiently. In this paper, we propose a non-parametric method using the stochastic watershed, allowing to estimate a 3D probability map of contours. Procedures allowing to extract final segmentation from this function are then presented.
A 39 year old male comes to the emergency room because of rapidly increasing pain in his left leg one hour after the injection of Flunitrazepam into a groin vessel. There is a history of drug abuse for more than 15 years. The left leg is cool and shows intense patchy cyanosis. The same skin discoloration is seen at the left lower abdomen and parts of the thigh. The leg is paretic but foot-pulses are detectable. Color-coded duplex-sonography of the left leg shows normal shaped arteries with regular flow. Regarding the veins there are post-thrombotic changes but no signs of actual thrombosis. The ECG shows sinus rythm. No source of emboli can be found by echocardiography. The laboratory tests reveal normal results except of anemia (Hb 9,6 g/dl, normocytic, normochromic). As an accidental intraarterial injection with a toxic/allergic insult to the vessel-walls has to be supposed the patient is treated besides of analgesics with systemic anticoagulation, high doses of cortison and calcium channel-blockers. With this therapeutic regimen the leg and the left lower abdomen improve gradually except for some toes which remain cyanotic. During the first days the patient develops signs of moderate rhabdomyolysis with swelling of the leg and an increase of creatincinase concentration in blood. After 12 days the left leg has normalised but the toes show further demarcation. They have to be amputated six weeks later. The accidental injection of drugs into the femoral artery may result in the clinical picture of acute limb ischemia without occlusion of the big vessels of the leg. This obviously occurs most often with benzodiazepins, especially when crushed tablets soluted in water are injected. Color-coded duplex sonography is able to show open vessels within minutes and prevents ineffective surgical interventions.
Acute vascular insufficiency following intra-arterial injection of a variety of drugs has been recognized for many years. The present study addresses the hypothesis that this vascular insufficiency may be due to vasospasm. Intra-arterial injections of logarithmic doses of drugs of abuse from the barbiturate, narcotic, non-narcotic analgesic, and amphetamine groups were studied in baboons. All drugs except amphetamine produced significant increases in femoral flow. Dextroamphetamine produced insignificant alteration in flow. Solid excipients, cornstarch, and talcum powder when injected intra-arterially decreased flow, and vascular obstruction was shown angiographically. These data suggest that vasospasm is not a primary response of intra-arterial injection of drugs of abuse.
Opioid peptides have been implicated in shock-associated hypotension. Our aim was to find out whether opioid agonists have direct vasodilator actions on vascular smooth muscle. The study was conducted on rat abdominal aortic rings. In rings precontracted with either norepinephrine, prostaglandin F2 alpha, or high potassium Krebs (HPK), the effects of the opioid agonists tested (morphine, U50488H, ethylketocyclazocine (EKC), and bremazocine) depended on the precontracting agent used. HPK-precontracted rings were relaxed by all agonists tested. In norepinephrine-precontracted rings, all caused contraction at low concentrations and relaxation at high concentrations except bremazocine, which caused only relaxation. In prostaglandin F2 alpha-precontracted rings, U50488H produced contraction at low concentrations and relaxation at high concentrations while EKC caused only relaxation and morphine or bremazocine caused only contraction. All relaxant responses were endothelium-independent and were antagonized by verapamil but not by a number of antagonists including naloxone. MR2266, propranolol, diphenhydramine, cimetidine, and indomethacin. They may reflect calcium channel blockade. Morphine-induced vasoconstriction was antagonized by high concentrations of of naloxone or mepyramine and may be due to release of histamine by a naloxone-sensitive mechanism. We conclude that (a) the opioid agonists tested exert direct actions on vascular smooth muscle; (b) the nature of the response depended not only on the agonist used and its concentration but also on the agent used to precontract the tissue; and (c) it is unlikely that direct actions of endogenous opioids contribute to the shock-associated hypotension because high doses were needed to elicit them.
Between 1972 and 1988, 48 patients with extremity ischemia after an intraarterial drug injection were treated with the following protocol: heparin, dextran 40, dexamethasone, elevation, and early mobilization of the extremity. A tissue ischemia score, derived by assessing the color, capillary refill, sensory function, and temperature of the extremity, was used to assess the ischemic injury. Each sign was scored either normal = 0 or abnormal = 1; then summed to provide the tissue ischemia score (range, 0 to 4). Twenty-four (50%) patients had an extremity tissue ischemia score less than or equal to 2. After treatment 22 of the 24 patients had a normal extremity, and 2 required limited digital amputations. In this group, outcome was comparable regardless of the time interval from intraarterial drug injection to treatment. Ten of 24 (50%) patients with an extremity tissue ischemia score greater than 2 had a normal extremity, 3 had a functional deficit, and 11 required digital amputations. Twelve of the 24 patients were treated within 24 hours and had a significantly superior outcome when compared to the 12 who were treated more than 24 hours after intraarterial drug injection (p less than 0.001, Fisher's exact test). The tissue ischemia score is a useful predictor of extremity outcome in patients with intraarterial drug injection. The outlined treatment protocol is effective in minimizing tissue injury caused by intraarterial drug injection. Institution of treatment within 24 hours of intraarterial drug injection is particularly important in patients who manifest severe ischemia.
Accidental, intraarterial injections of abused substances continue to be difficult management problems because of severe vascular complications. Vasospasm probably plays an important role in the pathophysiology of this injury, in addition to the more accepted roles of thrombosis and endarteritis. Three patients with severe, upper extremity ischemia after intraarterial injection of heroin, methamphetamine, and meperidine were treated with intraarterial tolazoline and streptokinase, along with intravenous heparin. All three patients had improved perfusion, assessed both clinically and by angiography. The responses to treatment in these patients demonstrated the roles of vasospasm and thrombosis in the origin of this injury and the therapeutic benefits of appropriately administered vasodilators and thrombolytic agents.
The paper describes five cases of accidental intraarterial injection of pharmacological drugs (diazepam or thiopentone) or dope (heroin) in an upper limb. Following a review of the physiopathological mechanisms which led to ischemic damage, the Authors outline a protocol of continuous pharmacological sympathicolysis in the affected limb, using repeated anesthetic blocks of the homolateral stellate ganglion.
Effect of the modification of morphine and nalorphine by glucuronate and sulfate conjugations at the 3- and 6-positions on the binding to opioid receptors was examined in a particulate fraction of rat brain. Competing potencies of both drugs against [3H]morphine and [3H]leucine enkephalin bindings were extremely decreased by either glucuronate or sulfate conjugation at the 3-position. On the other hand, the potencies of morphine and nalorphine against [3H]leucine enkephalin binding were considerably enhanced by the conjugations at the 6-position, whereas the potencies against [3H]morphine binding were decreased. These altered interactions of the conjugates at the 6-position with the two ligands were attributed to their enhanced binding to delta-receptor and reduced binding to mu-receptor by Hill plot and modified Scatchard analysis. Resulted comparable and simultaneous interactions with mu- and delta- receptors were assumed to be a cause of the enhanced mu-receptor-directed analgesia of morphine and elevated same receptor-directed antagonistic effect of nalorphine, which have been found previously in our laboratory.
Vascular complications resulting from drug abuse constitute a widespread and common clinical problem. A 3-year experience with 32 vascular complications (13 arterial, 19 venous) related to intravenous drug abuse is reported. Fourteen (48%) of the 29 patients in this series presented with septic vascular complications. These infections were a major cause of morbidity and mortality, resulting in two hospital deaths and a disrupted arterial repair. In addition, intra-arterial drug injection caused digital gangrene in two patients. Early recognition, diagnostic arteriography and venography, and planned therapeutic interventions are possible if a high level of suspicion is maintained.
WITH the ever growing problems of drug abuse, new patterns of complications have appeared. The increasingly common practice among drug abusers of intravenous injection of oral drug preparations has inevitably led to an occasional inadvertent intra-arterial injection. Although numerous reports in the literature describe the consequences of the intra-arterial injection of various parenteral preparations, only a few deal with the complications of the intra-arterial injection of oral medications (Table 1). Recent experience with three such cases, including two with tissue loss, prompted this report. Case Reports Case 1. A 32-year-old addict injected 2 50-mg pentazocine tablets (Talwin) dissolved in tap . . .
A case of inadvertent intra-arterial self-injection of crushed codeine tablets in an 37-year-old man, resulting in gangrene of an upper extremity, is presented. The problem studied was whether the gangrene was caused by the codeine or by one of the excipients found in the tablets. The cause of the gangrene was investigated in an experimental study. Each of the components of the tablet (codeine, lactose, gelatin, carboxymethyl cellulose, calcium stearate, talc, and microcrystalline cellulose) was injected into the femoral arteries of dogs. The results of the study clearly demonstrate that the unique component producing the gangrene was the micro-crystalline cellulose, while the injection of pure codeine was harmless. To date, the only reported deleterious effects of intravascular injection of micro-crystalline cellulose have been pulmonary embolism and granulomatosis. Some examples of drugs that include microcrystalline cellulose are methadone, methaqualone, oxcycodone, acetaminophen, aspirin with codeine, propoxyphene napsylate, meprobamate, and phenobarbital. Recently, the vulnerability of drug addicts who habitually inject drugs into veins to the accidental injection of an artery has been noted, and it seems likely that in the future the problem of intra-arterial injection will increase in severity. The literature of the last 40 years is reviewed, and a list of drugs known to have produced gangrene when injected intra-arterially is cited.
Acute ischemia of the hand following intra-arterial injection of a drug is an infrequent problem, but it requires urgent medical attention. In this report, a patient injected a nasal decongestant, oxymetazoline hydrochloride (Afrin), into his radial artery. This resulted in severe burning pain, and cyanotic, cold, and pulseless hand, suggestive of acute ischemia. Intra-arterial papaverine, nifedipine, anticoagulation with heparin, prednisone, and stellate ganglion block did not improve the hand circulation. Development of gangrene necessitated a disarticulation at the wrist joint. Diagnosis, complications, and therapeutic measures of acute hand ischemia secondary to intra-arterial drug injection are discussed.
The effects of intra-arterial injection of Temazepam are described in 11 drug abusers admitted over a 6 month period. All patients suffered severe ischaemia, and injection into the radial artery invariably resulted in tissue loss leading to amputation. The pathogenesis and options for treatment are discussed.
Arterial complications from inadvertent arterial puncture in intravenous drug abusers are well recognised. Most reports describe injury to the femoral artery with occasional reports of brachial and radial artery injury. A case of subclavian artery injury is described in this paper, and the pathophysiology and treatment of intraarterial drug injection discussed.
A rapid and selective reversed-phase high-performance liquid chromatographic assay with gradient elution and diode-array detection for diacetylmorphine, morphine, codeine, and their free and glucuronidated metabolites in plasma, was developed. After addition of ethylmorphine as internal standard the plasma samples were extracted using C18 ODS-2 solid-phase columns with a recovery better than 80%. The limit of quantitation using an injection volume of 2 microl was 25 ng/ml for each compound. The intra- and inter-day precision was better than 5%. The described method cannot only be used for pharmacokinetic studies but also for intoxication cases to monitor a wide range of opiates.
Intraarterial injections of crushed oral formulations of drugs may cause acute, severe ischemia, and gangrene. A 24-yr-old woman developed severe ischemia of the right hand following arterial self-injection of a crushed zolpidem tablet. The first four digits of her right hand remained gangrenous even after treatment with heparinization, vasodilators, prostacyclin, and hyperbaric oxygen. Zolpidem tablets contain microcrystalline cellulose, an approved structural element in tablets for humans that has also been found to be a potent embolic agent. Microvascular embolization related to the microcrystalline cellulose may have contributed to the ischemia of the patient's hand.