Management of Intravenous Infiltration Injuries.

BACKGROUND: Intravenous (IV) lines are ubiquitous in hospital settings. These lines can malfunction, leaking noxious contents into subcutaneous tissue. Existing literature describes invasive intervention and complex treatment protocols. These persist despite significant changes in the composition and administration of IV agents. The purpose of this study is to examine the consequences of IV infiltrations at a tertiary medical center to update protocols and treatment algorithms. MATERIALS AND METHODS: This study is an observational, retrospective chart review performed at a tertiary care medical center. All inpatient plastic surgery consultations for IV infiltration were reviewed from 2011 to 2017. Patients were included if IV infiltration was suspected or documented. Data were collected for each injury regarding patient demographics, substance, and intervention. RESULTS: The plastic surgery service evaluated 381 IV infiltration injuries from 2011 to 2017, with 363 meeting the criteria. Injuries per year progressively increased, with 32 consultations in 2011 and 102 consultations in 2017. The vast majority of injuries identified (91%) were treated with only elevation and observation. The minority consisted of wound care (7%) performed by nursing or any form of incision, aspiration, or antidote injection (2%) performed by the physician. Of the 363 injuries, the most common infiltrates were noncytotoxic (35%), radiographic contrast (27%), and known vesicants (18%). Interestingly, a large portion of consultations were requested by other surgical services (32%). CONCLUSIONS: Although there is an increase in expert involvement for cases of IV infiltration injuries, the vast majority of these injuries are managed with minimal intervention. This is most likely owing to recent changes that have decreased the potential for harmful infiltration. Contrary to existing literature, invasive intervention is almost never indicated.

Lesions Associated With Calcium Gluconate Extravasation: Presentation of 5 Clinical Cases and Analysis of Cases Published.

INTRODUCTION: Calcium gluconate extravasation is a process, which, while not common, occurs more frequently in neonatal intensive care units. The aim of this study is to present a number of cases of calcium gluconate extravasation, which have occurred in our hospital, and to carry out a review of those clinical cases published in the literature to obtain relevant epidemiological data. METHODS: Data were gathered on the medical histories of 5 patients who presented lesions secondary to calcium gluconate extravasation in our center. A review of the literature was also performed to include clinical cases of calcium gluconate extravasation already published. RESULTS: Data were collected on 60 cases published in 37 articles. Most patients (55%) were neonates. The average age of these neonates was 8 days. The commonest location of injuries was the back of the hand and wrist (42%). The 2 most frequent symptoms were the appearance of erythema (65%) and swelling/edema (48%) followed by the appearance of skin necrosis (47%), indurated skin (33%), and yellow-white plaques or papules (33%). Most cases are cured within a period of 3 to 6 months. Fifty percent of patients required surgery, and in 13% of cases, skin grafts were performed. The most frequent histological finding was the presence of calcium deposits. Other histological findings described were the presence of necrosis, lymphohistiocytic infíltrate, and granulomas. Most histological findings were located in the dermis. Most x-rays showing calcium deposits had been performed at 3 to 4 weeks. CONCLUSIONS: Calcium gluconate extravasation is a process, which, although infrequent, is associated with serious skin and soft-tissue lesions, mainly affecting infants. Further studies are needed to determine possible specific procedures to be carried out in these cases.

Extravasation injuries.

It is common for an intravascular catheter to be inserted to administer various types of therapy. Extravasation occurs frequently, and in the most severe cases plastic surgeons are often summoned to assess the extent of the injury and the possibility for reconstruction. The Department of Plastic and Reconstructive Surgery at Oslo University Hospital assesses approximately 15 severe cases of this type each year.

On the Use of DSC-MRI for Measuring Vascular Permeability.

BACKGROUND AND PURPOSE: Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. MATERIALS AND METHODS: We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. RESULTS: K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). CONCLUSIONS: Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Fully automatic segmentation of fluorescein leakage in subjects with diabetic macular edema.

PURPOSE: To create and validate software to automatically segment leakage area in real-world clinical fluorescein angiography (FA) images of subjects with diabetic macular edema (DME). METHODS: Fluorescein angiography images obtained from 24 eyes of 24 subjects with DME were retrospectively analyzed. Both video and still-frame images were obtained using a Heidelberg Spectralis 6-mode HRA/OCT unit. We aligned early and late FA frames in the video by a two-step nonrigid registration method. To remove background artifacts, we subtracted early and late FA frames. Finally, after postprocessing steps, including detection and inpainting of the vessels, a robust active contour method was utilized to obtain leakage area in a 1500-µm-radius circular region centered at the fovea. Images were captured at different fields of view (FOVs) and were often contaminated with outliers, as is the case in real-world clinical imaging. Our algorithm was applied to these images with no manual input. Separately, all images were manually segmented by two retina specialists. The sensitivity, specificity, and accuracy of manual interobserver, manual intraobserver, and automatic methods were calculated. RESULTS: The mean accuracy was 0.86 ± 0.08 for automatic versus manual, 0.83 ± 0.16 for manual interobserver, and 0.90 ± 0.08 for manual intraobserver segmentation methods. CONCLUSIONS: Our fully automated algorithm can reproducibly and accurately quantify the area of leakage of clinical-grade FA video and is congruent with expert manual segmentation. The performance was reliable for different DME subtypes. This approach has the potential to reduce time and labor costs and may yield objective and reproducible quantitative measurements of DME imaging biomarkers.

Quantitative volumetry of cement leakage in viscosity-controlled vertebroplasty.

STUDY DESIGN: This study was designed as a cohort study comparing a prospective sample to a historic control group. OBJECTIVE: The aim of the actual trial was to compare the rate of cement leakage by quantitative volumetry comparing viscosity-controlled and non-viscosity-controlled vertebroplasty. SUMMARY OF BACKGROUND DATA: Percutaneous vertebroplasty (PVP) is a widespread safe and effective technique in the treatment of osteoporotic compression fractures and vertebral metastatic lesions. However, cement leakage has been identified as a problem of this technique. The leakage rates are reported to range from 7% to 90%. The main influence factor for leakage has been demonstrated to be cement viscosity. Assessment of appropriate injection viscosity is highly subjective and observer dependent. Viscosity-controlled vertebroplasty (Vertecem system) has been developed to objectively measure cement viscosity before injection. It introduces a viscosimeter to measure the actual cement viscosity before injection into the vertebra, and therefore may prevent leakages resulting from low-viscosity cement injections. Despite more than 800 Pubmed citations on PVP, there is only 1 report on distinct measurement of cement leakage by semiquantitative volumetry. METHODS: A total of 111 vertebrae in 68 patients, in which PVP was performed for osteoporotic fractures, were included. Thirty-seven patients (76 operated vertebrae) were assessed prospectively using the viscosity-controlled vertebroplasty. The results were compared with a retrospective group of 31 patients (35 operated vertebrae) undergoing PVP without using a viscosimeter. RESULTS: : There were no significant differences between the 2 groups in the applied volume of cement per fractured vertebra (P=0.73). The frequency of cement leakage in viscosimete-assisted vertebroplasty was 42.1% and 58.3% in the historic group. Cement leakage into the basivertebral vein (type B), was detected in 6.6% with and in 11.1% without viscosimetry. CONCLUSIONS: The use of viscosity-controlled vertebroplasty led to a decrease in the leakage rate from 58.3% to 42.1%. Leakage into the basivertebral vein with the risk of compression of nerval structures was reduced to almost 50% when viscosimetry was performed. It revealed to be a helpful tool for more unexperienced surgeons to assess the appropriate viscosity for vertebroplasty.

Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects.

The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.

A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma.

Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. Poly(ethylene glycol) (PEG)ylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumour via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the 'PEG dilemma' must be addressed. In this review, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking of cellular uptake and endosomal release using functional devices such as specific ligands, cleavable PEG systems and endosomal fusogenic/disruptic peptides.

PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect.

As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic-co-glycolic acid) (PLGA) is a widely used polymer for fabricating 'nanoparticles' because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity.

Tumor delivery of macromolecular drugs based on the EPR effect.

Enhanced permeability and retention (EPR) effect is the physiology-based principal mechanism of tumor accumulation of large molecules and small particles. This specific issue of Advanced Drug Delivery Reviews is summing up multiple data on the EPR effect-based drug design and clinical outcome. In this commentary, the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating pharmaceutical nanocarriers is briefly discussed together with some additional opportunities for drug delivery arising from the initial EPR effect-mediated accumulation of drug-containing macromolecular systems in tumors.

Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect.

Polymeric micelles are ideally suited to exploit the EPR effect, and they have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies. NK012 is an SN-38-loaded polymeric micelle constructed in an aqueous milieu by the self-assembly of an amphiphilic block copolymer, PEG-PGlu(SN-38). The antitumor activity was evaluated in several orthotopic tumor models including glioma, renal cancer, stomach cancer, and pancreatic cancer. Two independent phase I clinical trials were conducted in Japan and the USA. In the preclinical studies, it was demonstrated that NK012 exerted significantly more potent antitumor activity with no intestinal toxicity against various orthotopic human tumor xenografts than CPT-11. In clinical trials, predominant toxicity was neutropenia. Non-hematologic toxicity, especially diarrhea, was mostly Grade 1 or 2 during study treatments. Total 8 partial responses were obtained. According to data of preclinical studies, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. Clinical studies showed that NK012 was well tolerated and had antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing in patients with colorectal cancer in Japan and in patients with triple negative breast cancer and small cell lung cancer in the USA.

The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect.

The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. For example, angiogenesis leads to high vascular density in solid tumors, large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. We demonstrated methods to enhance this effect artificially in clinical settings. Of great importance was increasing systolic blood pressure via slow angiotensin II infusion. Another strategy involved utilization of NO-releasing agents such as topical nitroglycerin, which releases nitrite. Nitrite is converted to NO more selectively in the tumor tissues, which leads to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses molecular mechanisms of factors related to the EPR effect, the unique anatomy of tumor vessels, limitations and techniques to avoid such limitations, augmenting tumor drug delivery, and experimental and clinical findings.

A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage.

The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.

The application of MRI for depiction of subtle blood brain barrier disruption in stroke.

The development of imaging methodologies for detecting blood-brain-barrier (BBB) disruption may help predict stroke patient's propensity to develop hemorrhagic complications following reperfusion. We have developed a delayed contrast extravasation MRI-based methodology enabling real-time depiction of subtle BBB abnormalities in humans with high sensitivity to BBB disruption and high spatial resolution. The increased sensitivity to subtle BBB disruption is obtained by acquiring T1-weighted MRI at relatively long delays (~15 minutes) after contrast injection and subtracting from them images acquired immediately after contrast administration. In addition, the relatively long delays allow for acquisition of high resolution images resulting in high resolution BBB disruption maps. The sensitivity is further increased by image preprocessing with corrections for intensity variations and with whole body (rigid+elastic) registration. Since only two separate time points are required, the time between the two acquisitions can be used for acquiring routine clinical data, keeping the total imaging time to a minimum. A proof of concept study was performed in 34 patients with ischemic stroke and 2 patients with brain metastases undergoing high resolution T1-weighted MRI acquired at 3 time points after contrast injection. The MR images were pre-processed and subtracted to produce BBB disruption maps. BBB maps of patients with brain metastases and ischemic stroke presented different patterns of BBB opening. The significant advantage of the long extravasation time was demonstrated by a dynamic-contrast-enhancement study performed continuously for 18 min. The high sensitivity of our methodology enabled depiction of clear BBB disruption in 27% of the stroke patients who did not have abnormalities on conventional contrast-enhanced MRI. In 36% of the patients, who had abnormalities detectable by conventional MRI, the BBB disruption volumes were significantly larger in the maps than in conventional MRI. These results demonstrate the advantages of delayed contrast extravasation in increasing the sensitivity to subtle BBB disruption in ischemic stroke patients. The calculated disruption maps provide clear depiction of significant volumes of BBB disruption unattainable by conventional contrast-enhanced MRI.

Non-invasive imaging of barriers to drug delivery in tumors.

Solid tumors often develop high interstitial fluid pressure (IFP) as a result of increased water leakage and impaired lymphatic drainage, as well as changes in the extracellular matrix composition and elasticity. This high fluid pressure forms a barrier to drug delivery and hence, resistance to therapy. We have developed techniques based on contrast enhanced magnetic resonance imaging for mapping in tumors the vascular and transport parameters determining the delivery efficiency of blood borne substances. Sequential images are recorded during continuous infusion of a Gd-based contrast agent and analyzed according to a new physiological model, yielding maps of microvascular transfer constants, as well as outward convective interstitial transfer constants and steady state interstitial contrast agent concentrations both reflecting IFP distribution. We further demonstrated in non small cell human lung cancer xenografts the capability of our techniques to monitor in vivo collagenase induced increase in contrast agent delivery as a result of decreased IFP. These techniques can be applied to test drugs that affect angiogenesis and modulate interstitial fluid pressure and has the potential to be extended to cancer patients for assessing resistance to drug delivery.

Modeling intravasation of liquid distension media in surgical simulators.

During therapeutic hysteroscopy and transurethral resection of the prostate, intravasation of the liquid distension media into the vascular system of the patient occurs. We present a model which allows the integration of the intravasation process into surgical simulator systems. A linear network flow model is extended with a correction for non-Newtonian blood behavior in small vessels and an appropriate handling of vessel compliance. We employ a fast lookup scheme in order to allow for real-time simulation. Cutting of tissue is accounted for by adjusting pressure boundary conditions for all cut vessels. We investigate the influence of changing distention fluid pressure settings and of the position of tissue cuts. In addition, we quantify the intravasation occurring with different approaches of fluid control, and we compare the performance of direct and iterative solvers applied to the non-linear system of the compliant model. Our simulation predicts significant intravasation only on the venous side, and just in cases when larger veins are cut. The implemented methods allow the realistic control of bleeding for short-term and of the total resulting intravasation volume for long-term complication scenarios. While the simulation is fast enough to support real-time training, it is also adequate for explaining intravasation effects which were previously observed on a phenomenological level only.

Rat model for anterior segment intraocular surgery induced blood-retinal barrier breakdown.

PURPOSE: To develop a practical rat model of blood-retinal barrier (BRB) breakdown induced by anterior segment intraocular surgery. METHODS: A 27-gauge needle attached to infusion tubing running to a bottle of balanced salt solution was inserted through the limbus into the rat anterior chamber. The pressure of the balanced salt solution was oscillated from 0 to 12 mm Hg above the atmospheric pressure for 30 times. The needle was removed and the anterior chamber was formed. Then the eye was exposed vertically to the light of the operating microscope. The contralateral eye was left untreated. The eyes were applied with ofloxacin ophthalmic solution after surgery. At several time points after surgery, the integrity of the BRB was assessed by fluorescence fundus angiography, optical coherence tomography, immunohistochemical staining for serum albumin and quantitative measurement using Evans blue as a tracer. RESULTS: The extravasation of fluorescein, the increased central retinal thickness, strong staining for albumin in the retina and substantially elevated retinal Evans blue leakage demonstrated BRB breakdown after anterior segment intraocular surgery. On the 1st day after surgery, the model group showed a statistically significant elevation in the retinal Evans blue leakage as compared to the contralateral control group and the normal control group. These increased and reached the peak on the 2nd day after surgery and decreased to the point that there was no significant difference as compared to the contralateral control group and the normal control group on the 7th day after surgery. CONCLUSIONS: This study establishes a practical rat model of BRB breakdown induced by anterior segment intraocular surgery.

The eggshell technique for prevention of cement leakage during kyphoplasty.

Cement extravasation during kyphoplasty occurs between 4% and 9%, a much lower incidence than with vertebroplasty. However, because of the potential complications of cement in and around the spinal canal, any egress of cement outside the vertebral body is extremely concerning. Aborting the procedure will cease the extraosseous leakage and minimize potential immediate complications. However, the cavity will remain unfilled and the fracture unstable. Rather than aborting, we have devised a technique, called the eggshell technique, to manage the patient's fracture once extravasation is noted so that the procedure can be safely completed.

Injury to the upper extremity caused by extravasation of contrast medium: a true emergency.

This retrospective clinical study, over a period of four years, includes 16 patients who had extravasation of iopromidum 623 mg (Ultravist 300) in the upper extremity during computed tomography (CT). Although conservative management is sufficient in most cases, seven patients were operated on. The mean time between extravasation and operation was 155 minutes. The most complicated postoperative course occurred when the operation was delayed 300 minutes after extravasation. When patients were treated early, there was no permanent postoperative impairment. Extravasation of contrast is an increasing cause of potential complications in the forearm as a result of the use of power injectors in CT. Immediate assessment by an experienced plastic surgeon followed by either conservative treatment or quick intervention if necessary may avoid serious damage.