Severe Extravasation Research Articles

Extravasation Screening and Severity Prediction from Skin Lesion Image using Deep Neural Networks.

Extravasation occurs secondary to the leakage of medication from blood vessels into the surrounding tissue during intravenous administration resulting in significant soft tissue injury and necrosis. If treatment is delayed, invasive management such as surgical debridement, skin grafting, and even amputation may be required. Thus, it is imperative to develop a smartphone application for predicting extravasation severity from skin image. Two Deep Neural Network (DNN) architectures, U-Net and DenseNet-121, were used to segment skin and lesion, and to classify extravasation severity. Sensitivity and specificity for predicting between asymptomatic and abnormal cases were 77.78 and 90.24%. For each severity in abnormal cases, mild extravasation attained the highest F1-score of 0.8049, followed by severe extravasation of 0.6429, and moderate extravasation of 0.6250. The F1-score of moderate-to-severe extravasation classification can improve by applying the our proposed rule-based for multi-class classification. These findings proposed a novel and feasible DNN approach for screening extravasation from skin images. The implementation of DNN-based applications on mobile devices has a strong potential for clinical application in low-resource countries. Clinical relevance- The application can serve as a valuable tool in monitoring when extravasation occurs during intravaneous administration. It can also help in the scheduling process across worksite to reduce the risks associated with working shifts.

Treatment of severe extravasation injury in a newborn by using tilapia fish skin: A case report.

Introduction and importancePeripheral venous catheterizations in newborns are associated with complications such as infections, phlebitis, vessel rupture and drug leaks or serum. Extravasation injury refers to the leakage of injected drugs from blood vessels causing damage to the surrounding tissues, skin necrosis, and sometimes amputation. Using tilapia fish skin (TFS) is one of the new strategies that have been used in wound management.Case presentationThis case is a 36-week- and 4-day-old male fetus with a birth weight of 1600 g, height of 40 cm, and head circumference of 31 cm who was born to a 25-year-old mother by cesarean section at Mahzad Obstetrics and Gynecology Hospital, Urmia, Iran. On the third day of hospitalization at neonatal intensive care unit (NICU), an extravasation injury occurred in the infant's left hand in size approximately 1 × 1 cm by peripheral catheter. Despite extensive intravenous antibiotic therapy and rinsing with normal saline, wound healing was not achieved. The necrotic area was bandaged by using of the tilapia skin. For this purpose, the area was first washed with normal saline for 5 min and then the tilapia skin was placed on the damaged skin for 10 days. After a month, the newborn's wound had completely healed.Clinical discussionInfants are more prone to extravasation injury than adults due to being more sensitive and thinner peripheral vessel walls.ConclusionThis case illustrates that tilapia fish skin may be a suitable alternative to other temporary skin cover dressings in premature newborns suffering from extravasation injury.

Drug Extravasation in a Large General Hospital in Hunan, China: A Retrospective Survey.

Background and AimDrug extravasation is one of the most common complications of intravenous therapy, which can lead to severe tissue injury if inappropriately treated. This study analyzes the current situation of extravasation and the risk factors affecting the severity of extravasation to provide a theoretical basis for carrying out prospective research, reducing the severity of drug extravasation, and strengthening the management of drug extravasation.Materials and MethodsWe retrieved the data on extravasation from January 2016 to December 2020 from the hospital’s safe infusion management system. We used nonparametric tests to assess the differences in the severity of drug extravasation among each variable and performed a multivariate analysis using multivariate ordered logistic regression.ResultsExtravasation occurred in 0.038% (263/694,043) of patients, including 203 cases of mild extravasation (77.2%), 57 cases of moderate extravasation (21.7%), and 3 cases of severe extravasation (1.1%). The main diseases of the patients with extravasation were cancer (24.7%), neurological-related diseases (19.4%), circulatory-related diseases (14.8%), and digestive-related diseases (14.1%); the main extravasated drugs were hypotonic or hypertonic drugs (31.9%) and contrast media (27.8%); the infusion tools of extravasation were indwelling needles (92.0%) and steel needles (8.0%). The multi-factor analysis showed that close to joints, patients’ age ≤6 or age >65, cancer, neurological-related diseases, circulatory-related diseases, antineoplastic agents, hypotonic or hypertonic drugs and strong acid or alkali drugs were independent risk factors for more severe extravasation. The nurses’ age and first identified by nurse were nurse-related factors that influenced the severity of drug extravasation.ConclusionTo prevent the occurrence of drug extravasation and reduce its severity, the nurses should strengthen the learning of emergency plans related drug extravasation, strengthen inspections of high-risk patients. Besides, the managers should strengthen the risk warning management of high-risk extravasated drugs.

Iodixanol activation of mast cells: Implications in the pathogenesis of iodixanol-induced delayed cutaneous adverse reactions

Iodinated contrast media (ICM) is widely used in radiological examination and interventional therapy. In the commonly used ICM, iodixanol is considered to be the safer one. However, compared with other ICMs, it has a higher incidence of delayed cutaneous adverse reactions. The underlying mechanisms are unclear. In this study, mice with positive allergic reactions were selected based on the mouse clinical allergy symptom score and skin and blood samples taken 1, 6, 24, 48, and 72 h after ICMs (6 g iodine/kg) injection for histological and blood analyses. ICMs-induced pseudo-allergic reactions were investigated through in vivo intravital vascular imaging and passive cutaneous anaphylaxis (PCA) not mediated by IgE and through, calcium imaging degranulation of mast cells (MCs), and western blot assays in vitro. Results shows iodixanol-induced systemic anaphylaxis caused severe extravasation of plasma proteins and degranulation of skin MCs, and increased levels of plasma histamine, cytokines and inflammatory chemokines. Mechanistically, iodixanol increases degranulation of MCs and promotes the synthesis of inflammatory factors by activating PLC-γ and PI3K-related pathways. Trigonelline inhibit iodixanol-induced MC-related pseudo-allergic reactions in vitro and in vivo. These results suggest that mice in the iodixanol group had a higher incidence of delayed cutaneous reactions, characterized by cytokine release over time and delayed cutaneous MC degranulation. Iodixanol’s delayed cutaneous adverse reactions may be due to a delayed phase of MC-related pseudo-allergic reactions. Trigonelline revealed anti-allergic activity in iodixanol-induced MC-related pseudo-allergic reactions.

Efficacy of combination of localized closure, ethacridine lactate dressing, and phototherapy in treatment of severe extravasation injuries: A case series.

BACKGROUNDThe management of severe extravasation injuries is still controversial. Extravasation injuries can be treated in many ways. AIMTo present a series of patients with severe extravasation injuries due to infusion who were managed with ethacridine lactate dressing combined with localized closure and phototherapy. METHODSIn this study, we evaluated the data of eight patients, including six from the Department of Burn, one (with colorectal carcinoma) from the Veteran Cadre Department, and one (with leukemia) from the Hematology Department. Of these, three patients were male and five were female. Age of the patients ranged from 10 mo to 72 years, including two children (10 and 19 mo of age). In this study, the infusion was stopped immediately when the extravasation was identified. The extravasation event was managed routinely using a blocking solution. A ring-shaped localized closure was performed using the blocking agents. Moreover, ethacridine lactate dressing and phototherapy were applied for 3-5 d. RESULTSIn this study, the drugs contained in the infusates were iodixanol, norepinephrine, alprostadil, amino acids, fat emulsion, cefoselis, cefoxitin, and potassium chloride + concentrated sodium chloride. All of the patients achieved complete healing after treatment and no obvious adverse reactions were observed. CONCLUSIONThe treatment of severe extravasation injuries using a combination of localized closure, ethacridine lactate dressing, and phototherapy resulted in satisfactory outcomes in patients.

Tissue distribution of epirubicin after severe extravasation in humans

PurposeAs critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose–toxicity relation.MethodsFrom six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).ResultsAfter extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.ConclusionSurgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.

Evaluation of an acetated Ringer-based contrast material mixture for postmortem computed tomography angiography

PurposeThe purpose of this study was to compare an established postmortem contrast medium mixture based on polyethylene glycol (PEG) to an isotonic crystalloid with acetated Ringer solution (AR) as the base, both mixed with water-soluble iodinated contrast medium for postmortem computed tomography angiography (PMCTA) with the aim to avoid alterations of the corpse during autopsy. Materials and methodsThe study included 20 cadavers; 10 had PMCTA with AR and 10 with PEG. PMCTA images were analyzed with respect to image quality, vascular contrast patterns and artifacts. Autopsy was evaluated for visual, organ, vessel and haptic alterations. The Wilcoxon rank sum test was used to search for differences in image quality between the two groups. Statistical significance was set at P<0.05. ResultsAR provided excellent contrast within the right coronary artery (P<0.001) but a lack of contrast within the left coronary artery (P=0.008) whereas PEG showed the opposite. A better image quality was observed in the PEG group by comparison with the AR group for right common carotid artery (P=0.03), left common carotid artery (P=0.01) and left coronary artery (P=0.008). No differences were found for ascending aorta (P=0.65), aortic arch (P=0.09), right circle of Willis (P=0.17), left circle of Willis (P=0.08), inferior vena cava (P=0.07) and abdominal aorta (P=0.08). Severe extravasation occurred in all (10/10; 100%) cadavers in the AR group but in none (0/10; 0%) in the PEG group (P<0.001). At autopsy, visual alteration with lilac discoloration of the face was observed in 4/10 cadavers (40%) in the AR group and in 9/10 cadavers (90%) in the PEG group (P=0.057). Haptic alterations were observed in 3/10 cadavers (30%) in the AR group and 10/10 cadavers (100%) in the PEG group (P=0.003). ConclusionAR results in contrast medium mixture extravasation in all cadavers, but PEG altered the autopsy more severely. Both carrier substances result in specific substance-related artifacts and dependent opacification of the coronary arteries, but PEG is recommended for PMCTA exclusively with regard to diagnostic imaging.

454P - Predictors of severity and comparison of CTCAE V3.0 vs V4.3 in assessing chemotherapy induced extravasation injuries

BackgroundExtravasation is an important Adverse Event in chemotherapy, which is evaluated using CTCAE (Common Terminology Criteria for Adverse Events) grading scale. This study focuses on predicting risk factors and comparing CTCAE v3.0 and 4.3 in assessing chemotherapy-induced extravasation. MethodsAn observational study was conducted in medical oncology wards of a tertiary care hospital among adult patients receiving parenteral chemotherapy. European society of medical oncology – European oncology nursing society (ESMO-EONS) guidelines was used to classify chemotherapeutic agents. Significant risk factors were determined using binary logistic analysis. Spearman’s rank correlation coefficient and Wilcoxon’s sign rank test was applied to evaluate the difference between CTCAE v3.0 and v4.3. ResultsA total of 46 patients were enrolled in the study. According to CTCAE v4.3, amongst the 46 patients who experienced extravasation 30 presented with Grade II and the rest 16 with Grade III severity. Patients aged above 60 years showed significance (OR: 2.236, p = 0.007), and females were prone to severe extravasation injury (OR: 2.713, p = 0.010). Ambulation was found to be a major risk factor (OR: 4.66, p = 0.001). Patients with comorbidities had higher chances of getting severe extravasation (OR: 3.009, p = 0.029) and irritants were found to be predominant in worsening it (OR: 2.24, p = 0.007). The Spearman’s rank correlation coefficient established a good association in EV grades between both versions of CTCAE (rho=0.877, p = 0.000). Wilcoxon’s Rank test revealed a significant difference between the two. (p = 0.0003). ConclusionsThe severity of EV depends on early identification of symptoms, patient related factors and nature of drug. This information is pivotal to work towards a scenario of better-prevented and managed events of EV. The updated versions of CTCAE (v4.3 and v5) are better fit to use for accurate scoring of severity. Legal entity responsible for the studyAll Authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Extravasation of iodinated contrast medium in cancer patients undergoing computed tomography.

ObjectiveThe aim of this study was to evaluate the incidence of extravasation of iodinated contrast medium (ICM) at the site of intravenous injection in oncology patients submitted to computed tomography (CT).Materials and MethodsThis was a retrospective, descriptive, single-center study that evaluated all patients who underwent CT with ICM administration and presented ICM extravasation, at a cancer center, between January 2010 and December 2015.ResultsDuring the study period, we evaluated a total of 99,076 ICM injections and identified 199 cases of extravasation, the incidence rate therefore being 0.20%. Among the patients who presented extravasation, the mean age was 59.22 years and 60% were female. The extravasation was classified as mild in 94.10% of the patients and as moderate in 5.90%. There were no cases of severe extravasation in the sample.ConclusionThe incidence of ICM extravasation in cancer patients submitted to CT in the present study was similar to that reported for the general population, according to other studies in the literature. The vast majority of cases of extravasation were considered mild, and no severe cases were observed in the study sample.

Severe Extravasation Injuries in Neonates: A Report of 34 Cases.

Extravasation injuries are a common and challenging problem in hospitalized newborns. Accidental infusion leakage into the surrounding tissues in immature infants may frequently result in skin necrosis, with significant risk of functional and cosmetic impairment. In the present study we reviewed 34 cases of severe extravasation injuries occurring in 1,409 neonates hospitalized in a single neonatal unit over 24 months (incidence 2.4%). Total parenteral nutrition solutions were involved in most cases. All patients were treated within 30 minutes after the injury was recorded using a flush-out technique with normal saline irrigation and occlusive paraffin dressings of the infiltrated area. The majority of injuries affected preterm, low-birthweight infants (mean gestation 32 wks + 6 days, mean birth weight 1,885 g), with a mean age at the time of injury of 11.6 days and a mean weight of 2,045 g. Neither gestational age (p = 0.87) or birthweight significantly affected (p = 0.07) the incidence of extravasation injuries, although the incidence of skin necrosis had a significant correlation with gestational age (p = 0.009) and birthweight (p < 0.001). All patients responded well to treatment and their wounds healed uneventfully within a maximum of 25 days without the need for secondary surgery for skin coverage. Extravasation injuries in extremely preterm and low-birthweight infants are more likely to lead to skin necrosis. Peripheral venous catheterization should be performed with caution in these patients to prevent such injuries. Immediate irrigation with normal saline is recommended to reduce toxic sequelae in the infiltrated area.

A Cadaver Study to Compare Vertebral Augmentation With a High-viscosity Cement to Augmentation With Conventional Lower-viscosity Cement

Comparison of extravasations in fractured cadaver vertebrae augmented with commercial low-viscosity versus high-viscosity cements. Use of high-resolution, 3-dimensional (3D) imaging to test the hypothesis that high-viscosity cements can reduce the type and severity of extravasations after vertebral augmentation procedures. Cement extravasations are one of the primary complications of vertebral augmentation procedures. There is some evidence that high-viscosity cements might reduce extravasations, but additional data are needed to confirm the early findings. A range of vertebral fractures were created in fresh human cadavers. One group was then augmented with a low-viscosity polymethylmethacrylate (PMMA)-based cement and the other group injected with high-viscosity PMMA-based cement. High-resolution computerized tomography exams were obtained, and extravasations were assessed using 3D volume renderings. The type and severity of extravasations were recorded and analyzed. The proportion of vertebrae with any type of extravasation through the posterior wall to the spinal canal, into small vessels laterally or anteriorly, through the endplates, or anywhere around the body was not significantly different between the high-viscosity and low-viscosity groups. There was significantly less severe extravasation through the endplates (P=0.02), and a trend toward less severe extravasation through vessels (P=0.06) with the high versus low-viscosity cements. In agreement with previous research, high-viscosity PMMA-based cement may help to reduce the more severe forms of extravasations after vertebral augmentation procedures in newly fractured vertebrae.

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin: Erratum

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin: Erratum

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin

Dexrazoxane is now authorized for the treatment of anthracycline extravasations. Several clinical cases of doxorubicin extravasation treated with dexrazoxane have been reported to date, but detailed cases have not been published. We report a case of a successful dexrazoxane treatment for a potentially severe extravasation of concentrated doxorubicin. We also describe objective outcome of this treatment, drug tolerance to dexrazoxane and long follow-up. A 29-year-old man diagnosed with Hodgkin's lymphoma was prescribed a regimen including 90 mg of doxorubicin in a 50 ml infusion using a reduced occlusion infusion pump. After this infusion, the patient complained of pain around the site of injection and presented a 10x6-cm swollen area with erythema and inflammation. A significant portion of doxorubicin was extravasated. Dexrazoxane was prescribed as an antidote. Side effects of dexrazoxane were restricted to reversible hematological toxicity, nausea, and vomiting. The next day, the inflammation of the extravasation area was reduced. On day 7, a painless mild induration in the extravasated area was the only remaining sign of the extravasation. On day 40, an arm nuclear magnetic resonance image showed no focal injuries. At 6-month follow-up, the patient has no sequelae. The two risk factors that could have increased the severity of the extravasation are the use of an infusion pump and the high drug concentration. Dexrazoxane proved to be effective and moderately well tolerated. A dexrazoxane stock in oncological facilities could help to promptly handle emergencies like this. Anthracyclines can be administered using reduced occlusion infusion pumps, but it seems preferable to always administer a free-running infusion to minimize accidents like this one.

CT contrast extravasation in the upper extremity: Strategies for management

Introduction Extravasation of CT scan contrast media into upper extremity subcutaneous tissue is a relatively frequent complication of injection. Potential sequelae of extravasation include compartment syndrome, skin sloughing, and necrosis. Many institutions institute protocols requiring inpatient plastic surgery consultations immediately following extravasation injury to the upper extremity. We hypothesize that conversion to non-ionic contrast media for contrast CT studies has greatly reduced the incidence of severe extravasation injuries, and may alleviate the need for routine hand surgery consultations. Methods Records from 102 consecutive CT contrast media extravasation injuries were identified. Data acquired from a single institution included type and amount of contrast extravasated, anatomic location, post-procedural clinical symptoms, whether consult was obtained, and final recommendations and outcome. Results In 102 consecutive cases, immediate surgical therapy was necessary in 0. Non-ionic medium was used in 94% of these cases, and ionic dye was used in 6%. Extravasation of less than 100 cc occurred in 90%, and only 10% were greater. Plastic surgery consultation was immediately obtained in 42% of cases. Factors prompting consultation included extravasation >30 cc, and the presence of erythema or induration. Trends for consultation remained without discernable pattern when patients were stratified by age, amount of extravasate, or anatomic location. Conservative management was recommended in all cases. This included elevation of the extremity, frequent pulse and sensation exams, local message, and temporary splinting. There were no secondary complications requiring surgical intervention. Conclusions Extravasation of non-ionic CT contrast media appears to be innocuous and can be treated with conservative therapy. Plastic surgery consultation should be obtained when there are obvious signs of skin and soft tissue compromise or symptoms of compartment syndrome.

Reoperation versus observation in men with major bleeding after radical retropubic prostatectomy

Objectives To compare the postoperative and quality-of-life outcomes for men experiencing major bleeding after radical retropubic prostatectomy that was managed with reoperation or observation. Methods A total of 916 men underwent radical retropubic prostatectomy by a single surgeon between October 2000 and August 2004. Of the 916 men, 15 (1.6%) experienced major bleeding, defined as the transfusion of 3 U or more of allogeneic blood within the first 36 hours after radical prostatectomy. The outcomes were compared between the 5 men undergoing reoperation (group 1) and the 10 men whose bleeding was managed with observation (group 2). Results The mean total number of allogeneic blood units transfused was significantly greater in group 1 (7.4 U) than in group 2 (4.1 U; P = 0.002). Group 1 also experienced a significantly longer hospital stay (4.6 versus 2.6 days). Those men undergoing reoperation had a significantly lower probability of moderate to severe extravasation on initial cystogram compared with group 2 (0% versus 70%). In addition, the urinary catheter was indwelling for a shorter interval (9.6 versus 23.5 days). We also found a suggestion of better continence in group 1. Conclusions Reoperation for major bleeding after radical retropubic prostatectomy facilitates both healing of the vesicourethral anastomosis and removal of the urinary catheter.

Early catheter removal 3 days after radical retropubic prostatectomy

We investigated the feasibility and safety of the early removal of urethral catheters 3 days after radical retropubic prostatectomy. Seventy consecutive patients underwent radical retropubic prostatectomy with the intent of early catheter removal on postoperative day (POD) 3. Catheter removal was based on postoperative cystograms performed on POD 2. Patients were analyzed using a validated prostate cancer specific questionnaire (University of California, Los Angeles Prostate Cancer Symptom Index) to determine quality of life outcomes. Multiple logistic regression analysis was also used to evaluate if any of the preoperative or intraoperative parameters were able to predict the success of early catheter removal after radical retropubic prostatectomy. The catheter was removed on POD 3 in 67 of 70 patients (97%) excluding three patients with moderate or severe extravasation on postoperative cystograms. Of the 67 patients, 53 (76%) were successful in early catheter removal, but the remaining 14 (24%) patients experienced urinary retention within 48 h and were treated with simple catheter replacement for 1 or 2 days. Two patients developed anastomotic strictures 3 and 4 months postoperatively, which were managed by dilation alone. Multiple logistic regression analysis showed that no leak during an intraoperative leak test was the only independent predictor of success for early catheter removal (P = 0.0069; odds ratio, 6.667; 95% confidence interval, 1.682-26.428). The present study revealed that early catheter removal 3 days after radical retropubic prostatectomy is feasible in patients who show a negative intraoperative leak test. Postoperative monitoring of more patients is needed to determine if the early catheter removal is widely applicable.

Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential

We present here a new cell line, NOR-P1, established from a metastatic subcutaneous tumor of a patient with pancreatic cancer. The cells show rapid growth in culture with a doubling time of 16 h and high migration activity. Genetic and molecular analyses revealed high telomerase activity and a mutation in the K- ras oncogene. Of particular interest, the cells express markedly elevated mRNA levels of angiogenic factors, vascular endothelial growth factor and platelet-derived growth factor, as well as other tumor growth-related factors. Subcutaneous transplantation of the NOR-P1 cells into nude mice formed solid, hemorrhagic tumors which were histologically diagnosed as adenocarcinoma with dense blood vessels and severe extravasation of blood. Furthermore, when NOR-P1 cell suspension was injected directly into the pancreas of nude mice, the cells grew rapidly to form intra-pancreatic tumors associated with liver metastases and peritoneal dissemination that resulted in cachexia and subsequent death. These properties suggest that NOR-P1 is an aggressive pancreatic cancer cell line with a high metastatic potential and may serve as a useful experimental model for studying tumor angiogenesis and metastasis of pancreatic cancer.

LEFLUNOMIDE CONTROLS REJECTION IN HAMSTER TO RAT CARDIAC XENOGRAFTS

Leflunomide is an isoxazole derivative that has the ability to prevent acute rejection of cardiac, renal, and skin transplants in strongly rejecting rat models. Furthermore, leflunomide is able to interact synergistically with CsA to inhibit allograft rejection and also reverse ongoing allograft rejection. In vitro studies suggest that the mechanism of action of leflunomide is via an interruption of cytokine signaling in T cells. This study defines the ability of leflunomide to prevent and reverse rejection of concordant xenografts. One hundred nine adult Lewis rats in 13 groups received abdominal heterotopic cardiac transplants from Golden Syrian hamsters. The xenograft survived 3.9 +/-0.3 days without treatment. When leflunomide was given at 2.5, 5, 10, 15, or 20 mg/kg by gavage daily, the cardiac xenograft survivals were 5.0 +/- 0.6, 8.0 +/- 3.0, 52.0 +/- 20.2, 76.5 +/- 21.14, and 58.9 +/- 28.1 days, respectively. The survival rates were 4.0 +/- 0 and 27.7 +/- 28.7 days when CsA was given at 10 and 20 mg/kg i.m., respectively. The combination of CsA at 10 mg/kg with leflunomide at 10 mg/kg or 5 mg/kg prolonged cardiac xenograft survival to 106.0 +/- 50.2 days and > 90 days, respectively. There were no observable side effects in the latter combination. Histologic studies of untreated graft hearts 4 days after transplantation revealed infarction of myocardium and severe RBC extravasation. In contrast, the rejected hamster hearts from long-term survivors showed massive mononuclear cell infiltration and myocardium fibrosis in contrast to the early rejected picture. Therapy with leflunomide begun on day 2 reversed these rejection responses by day 6. In addition, the increase in allospecific IgM titers observed on day 2 was reversed, and the allospecific IgM to IgG isotype switch that occurred in untreated animals was prevented by leflunomide. These observations demonstrate that leflunomide, at nontoxic doses, effectively controlled acute rejection of concordant xenografts and synergistic immunosuppressive effect was achieved with leflunomide and CsA.

Direct Phlebography for Visualization of the Deep Veins in the Lower Extremities

A new method of phlebography, which the authors have named "direct phlebography," was developed as a means of obtaining accurate information on the deep vein system, as well as on the communicating veins in the lower extremities. This method consists of two techniques: one is a retrograde insertion of a catheter into the deep veins and the other is a direct injection of the contrast medium into the deep veins. For these techniques, use of a thin, soft guidewire and catheter; injection of a low-osmolar contrast medium; and systemic administration of heparin are important. In cases of varix cruris, the deep veins and the insufficient communicating veins were clearly visualized by this method. In cases of deep vein thrombosis, a "narrowed" but patent common or superficial femoral vein was detected, which had often been diagnosed as "occluded" by conventional ascending phlebography. The deep femoral vein was usually patent. The authors have used this method in 54 limbs, but no serious complications such as venous valve injury, severe extravasation, or thrombus formation have been encountered so far, except for a small extravasation in 1 patient with superficial femoral vein thrombosis. This new method, used to visualize the deep vein system directly, is thought to provide correct and useful information about the lesions in the deep vein system of the lower extremities.

Antioxidant enzymes reduce loss of blood-brain barrier integrity in experimental optic neuritis.

We studied the effect of antioxidant enzymes on the loss of integrity of the blood-brain barrier in the optic nerves of strain-13 guinea pigs with chronic experimental allergic encephalomyelitis, a demyelinating disorder with neurologic and histopathologic characteristics similar to multiple sclerosis. Animals with experimental allergic encephalomyelitis received daily intraperitoneal injections of either preservative-free saline (group 1), catalase (group 2), or glutathione peroxidase (group 3) for 2.2 months after the onset of appendicular paralysis. Following intravascular administration, extravascular leakage of horseradish peroxidase was histopathologically graded as mild, moderate, or severe within the optic nerve head and myelinated retrolaminar nerve. Severe extravasation of horseradish peroxidase was exclusive to group 1, in addition to moderate and mild leakage. In groups 2 and 3, leakage of horseradish peroxidase was infrequent, and when detected, it was graded as mild. Detoxification of hydrogen peroxide with catalase and glutathione peroxidase substantially reduced horseradish peroxidase leakage in experimental optic neuritis, suggesting a role for hydrogen peroxide and its reactive by-products in the pathogenesis of increased vascular permeability of the blood-brain barrier in experimental allergic encephalomyelitis.