The Infusion Nurses Society (INS) established a

Transcription

1 The Art and Science of Infusion Nursing Development of an Evidence-Based List of Noncytotoxic Vesicant Medications and Solutions Infusion Nurses Society Vesicant Task Force Lisa A. Gorski, MS, RN, HHCNS-BC, CRNI, FAAN Marc Stranz, PharmD Lynda S. Cook, MSN, RN, CRNI James M. Joseph, MPH, BSN, RN, CRNI, VA-BC Kathy Kokotis, MBA, BS, RN Pam Sabatino-Holmes, MSN, ARNP, CRNI Lori Van Gosen, MSN, RN, PCNS-BC, CRNI, VA-BC ABSTRACT Infiltration of a vesicant medication, defined as extravasation, may result in significant patient injuries. The first step in preventing extravasation is the identification and recognition of vesicant medications and solutions. Because there is no list of noncytotoxic vesicants as established by a professional organization, the Infusion Nurses Society, as the global authority in infusion nursing, identified the need to address this gap. A task force was formed for the purpose of creating an evidence-based list of noncytotoxic vesicant medications and solutions. Key words: extravasation, infiltration, noncytotoxic, vesicants The Infusion Nurses Society (INS) established a task force (TF) with the goal of developing an evidence-based list of noncytotoxic vesicant medications and solutions. It is well recognized that infiltration of a vesicant drug, defined as extravasation, may result in patient injuries that range from prolonged length of stay, rehospitalization, and long-term treatment requirements to permanent functional impairment and even loss of limb. Oncology nurses who administer antineoplastic medications are well educated in vesicant drugs and extravasation prevention as this is an expectation of oncology practice. 1 There are also available lists of cytotoxic vesicants as identified by the Oncology Nursing Society. 2,3 Outside of oncology practice, there is no list of noncytotoxic vesicants as established by a professional organization. While some health care organizations provide such lists, many do not, and clinicians are frequently unaware of vesicant medications and the risks and consequences Lisa A. Gorski, MS, RN, HHCNS-BC, CRNI, FAAN, has worked as a clinical nurse specialist at Wheaton Franciscan Home Health and Hospice since She served as president of the Infusion Nurses Society between 2007 and 2008, is the chairperson of the 2016 INS Standards of Practice Committee, has published multiple journal articles and books, and presents nationally and internationally on a variety of infusion nursing topics. Marc Stranz, PharmD, is vice president of the Elwyn Pharmacy Group in Philadelphia. He is a nationally recognized speaker and authority on infusion care, including clinical services and regulatory compliance. He has served on many committees for a variety of professional organizations, including INS, National Home Infusion Association, Association for Vascular Access, National Quality Forum, and American Society for Parenteral and Enteral Nutrition. Lynda S. Cook, MSN, RN, CRNI, is a clinical outcomes specialist for 3M Critical and Chronic Care Solutions Division where she serves as a nurse educator focusing on intravenous site management and outcomes. She is also a speaker and author and addresses many areas of infusion care. James M. Joseph, MPH, BSN, RN, CRNI, VA-BC, is the coordinator for vascular access services at Ohio State University Wexner Medical Center and The Ross Heart Hospital in Columbus, Ohio. He has implemented multiple clinical practice initiatives and guidelines in the organizations, including ultrasound-guided short peripheral catheter placement, a database for peripherally inserted central catheters and short peripheral catheters, vascular access device selection guidelines, and declotting protocols. Kathy Kokotis, MBA, BS, RN, is a published author and has presented nationally and internationally on a variety of topics related to vascular access, including peripherally inserted central catheter teams, vascular access assessment, and economics. She is an employee of Bard Access Systems. Pam Sabatino-Holmes, MSN, ARNP, CRNI, is the advanced vascular access clinical nurse educator at Baptist Hospital of Miami. She has conducted multiple research studies. She started the South Florida INS Chapter and served as its president and presidential advisor from 2012 to She has written and implemented multiple vascular access practice guidelines, policies, and procedures in Baptist Health System. Lori Van Gosen, MSN, RN, PCNS-BC, CRNI, VA-BC, is a pediatric clinical nurse specialist who built the pediatric vascular access team at the Johns Hopkins Children s Center. She has written and implemented pediatric vascular access policies, practice guidelines, and clinical practice initiatives for the Children s Center. She is a published author and has presented at a national vascular access conference. The authors have completed and submitted a form for disclosure of potential conflicts of interest. L.G. reported relationships with ivwatch, BD, 3M, Covidien, and Genentech. Corresponding Author: Lisa A. Gorski, MS, RN, HHCNS-BC, CRNI, FAAN, N Hawks Glen Ct, Mequon, WI ( lisagorski@hotmail.com ). DOI: /NAN Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

2 of extravasation. INS, as the global authority in infusion nursing, identified the need to address this gap based on the following premise: the first step in preventing extravasation is the identification and recognition of vesicant medications and solutions. Others have also identified the importance of knowing and identifying potential vesicants as critical in extravasation prevention. 4,5 The scope of work for this TF was limited to creating an evidence-based list of noncytotoxic vesicant medications and solutions and developing a clinical practice tool that outlines risk reduction strategies including early recognition of signs and symptoms of extravasation. Treatment and interventions for extravasation were outside the scope of work and thus were not addressed by the TF. SEARCH STRATEGY AND DEVELOPMENT OF VESICANT LIST The first step performed by the TF was development of a list of all medications and solutions as labeled by the US Food and Drug Administration (FDA) for infusion using the US National Library of Medicine. Additional resources included a pharmaceutical reference and an intravenous (IV) medication reference book. 6,7 This review isolated medications having characteristics related to extravasation: tissue necrosis, sloughing, blistering, phlebitis, thrombophlebitis, and patient pain. Only noncytotoxic medications were retained on this list. Following this step, the original plan of the TF was to perform a systematic review of the literature for the purpose of identifying noncytotoxic vesicants. A medical librarian completed the literature search, which was shared with the TF. However, soon after beginning the literature review, Le and Patel published a systematic literature review of noncytotoxic vesicants in early Based on this, the TF decided to use this and 3 additional recent literature reviews as the primary sources for developing the list. 5,8,9 An additional literature search using the search terms of extravasation, infiltration, and vesicants was completed prior to final completion of the TF work and submission of this manuscript. DEFINITIONS There is often confusion among nurses related to the definitions of vesicant, irritant, and extravasation. For example, Clark and colleagues defined extravasation as an inadvertent administration or leakage of infusate into the extravascular tissue, 5(p38) while clearly stating and acknowledging that there are other definitions. 5 Definitions from relevant infusion textbooks and infusion groups were reviewed and discussed both within the TF and with the INS Standards of Practice Committee The groups recommended retaining the current INS definitions of vesicant and extravasation, which remain unchanged in the 2016 Infusion Therapy Standards of Practice (the Standards ) 15 : Vesicant: An agent capable of causing blistering, tissue sloughing, or necrosis when it escapes from the intended vascular pathway into surrounding tissues 15(pS155) Extravasation: The inadvertent infiltration of vesicant solution or medication into the surrounding tissue 15(pS149) Working with the Standards of Practice Committee, the TF recommended the following revision of the definition of irritant, which is now in the glossary of the Standards : an agent capable of producing discomfort (eg, burning, stinging) or pain as a result of irritation in the internal lumen of the vein with or without immediate external signs of vein inflammation. 15(pS151) In very simple terms, vesicants cause severe damage when the agent escapes from the vein, and irritants may cause damage within the vein. However, it must also be recognized that damage within the vein can lead to infiltration and extravasation. Mechanisms of extravasation are addressed elsewhere. 9,16 LITERATURE REVIEW Clark and colleagues focused on the risk of harm from extravasation among pediatric patients. 5 They performed a systematic literature review defining their search terms and filtering for English language and children up to age 18. A total of 273 articles were reviewed, and 65 addressed permanent harm due to peripheral IV-related extravasation. Of these, the majority of citations (75%) were single and multiple case reports; the rest included a variety of research studies. They also reviewed 8 articles that provided lists of drugs with known or suspected risk for injury with extravasation. This was done for the purpose of identifying risk based on expert opinion when there were no published cases of harm. They categorized the risk of peripherally administered infusates using a framework of red (higher risk), yellow (intermediate risk), and green (lower risk) based on the literature review, as well as local data, experience, and calculated ph and osmolarity measurements. Of note, based on their definition of extravasation, the list also includes irritant medications without published evidence of harm, based on infusate characteristics and expert opinion. Le and Patel performed a systematic literature review defining the search terms and using a time frame from 1961 through January They used the INS definition of extravasation and defined vesicants as agents that damage soft tissue by causing blistering and tissue necrosis. Acknowledging the problem of inconsistent definitions within the literature, phlebitis and infiltration were included in their search terms, which also included extravasation and soft tissue injury. They found 232 extravasation cases that involved 37 medications and solutions. Of note, a number of the medications included a citation describing only a single case. Reynolds and colleagues performed a literature review focusing specifically on effective treatment of extravasation to reduce injuries. 9 INS definitions of extravasation VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 27

3 TABLE 1 Evidence Table: Peripheral IV Administration of Vancomycin: Studies and Case Reports of Complications Citation/ Country/Strength of Evidence Bohm and Wong, USA SOE: V Caparas and Hu, USA SOE: III Type of Evidence/ Study Design Research Question/ Purpose Sample/Setting Methodology Results/Findings/Comments Case report N/A 72-year-old woman: peripheral catheter placed in proximal right upper extremity. On day 3 of hospitalization, extravasation of vancomycin occurred. Painful vesicles erupted in location of extravasation starting about 2 hours after extravasation. Erythema, edema, and hyperpigmentation present Randomized clinical trial Compare administra on of vancomycin via PICC vs midline catheter N = 54 hospitalized adult patients requiring short-term IV vancomycin (2 or more doses but < 6 days) Patients randomized to either a PICC (n = 25) or midline (n = 29) Excluded: patients with contraindications to vancomycin or the intended VAD; renal status precluded vascular access in upper extremity Researchers did not report power analysis. N/A Vancomycin-induced linear IgA LABD is a well-recognized adverse reaction. This case was cited as unique, as it was a localized reaction after a reported extravasation. Data collec on: Demographic and clinical information; all complications recorded Patients observed at least once per day Vancomycin administered over at least 60 minutes via infusion pump; concentra on 4 mg/ml Patency ensured by blood aspiration and flushing with 0.9% NaCl; if no blood return, catheter assessed for position via ultrasound Current prac ce: SPCs, midline catheters, and PICCs were all used rou nely to administer vancomycin at the authors hospital at the me of the wri ng. No significant differences in groups with respect to age, gender, administration of other antibiotics, and average number of days receiving vancomycin Both groups had some patients (29%-32%) receiving vancomycin for more than 5 days; not significant Mean PICC dwell time: 6.3 days (average age 69) Mean midline dwell time: 5.8 days (average age 72) No significant differences in total complications (18% PICC; 20% midline) No phlebitis or thrombosis in either group No significant difference in infiltrations (0: PICC; 3 [10%]: midline); infiltrations rated as Grade I, based on INS Infiltration Scale) 31 Drouet et al, France SOE: IV In vitro study Under in vitro condi ons simula ng clinical vancomycin use: assess endothelial cell viability to determine factors related to local toxicity HUVEC exposed to vancomycin doses according to concentration and time frames: 1 to 10 mg/ml over 24 hours 0.5 to 7.5 mg/ml over 24, 48, and 72 hours Control: HUVEC exposed to 0.9% NaCl adjusted to same ph To compare con nuous infusion and intermi ent infusion from 1 to 2.75 g/day, we used a vancomycin solu on at fixed concentra ons ranging from 1.5 to 5 mg/ ml for con nuous infusion, and from 4 to 11.5 mg/ml in 2, 1-hour periods for intermi ent infusion. 30(p930) HUVEC viability was measured using percentage cell death a er 24 hours of contact with vancomycin. Assessment of vancomycin ph on cell toxicity was conducted with doses of 5 and 7.5 mg/ml HUVEC death occurred at higher concentrations and longer time exposures to vancomycin Dose dependent: significant increase in cell death after 24 hours at 2.5 mg/ml ( P <.01) and 50% cell death at 5 mg/ml and higher ( P <.01) Time dependent: more cell death after 48 and 72 hours of treatment than after 24 hours ( P <.01) ph: Vancomycin toxicity not induced by acidic ph ( con nues ) 28 Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

4 TABLE 1 Evidence Table: Peripheral IV Administration of Vancomycin: Studies and Case Reports of Complications ( Continued ) Citation/ Country/Strength of Evidence Hoelen et al, Netherlands SOE: V Mowry and Hartman, USA SOE: IV Type of Evidence/ Study Design Research Question/ Purpose Sample/Setting Methodology Results/Findings/Comments Case report N/A 63-year-old; SPC inserted in dorsum of left foot. IV vancomycin administered (no other drugs through SPC; only 0.9% NaCl drip). After 48 hours, progressive skin lesion in regional vascular bed of SPC with leg swelling and redness. Ischemic lesion developed after 72 hours. 22 Retrospective observational, before and after design Evaluate the incidence of thrombophlebi s with peripheral administra on of amiodarone and vancomycin Determine if IV amiodarone concentra on influenced occurrence of SPC thrombophlebi s independent of IV vancomycin Hospitalized, adult cardiothoracic surgical patients > age 18 admitted to the acute care telemetry unit who received only amiodarone, only vancomycin, neither, or both N = 2423 patient records N = 2832 infusion episodes Study period: May 2004-March 2006 Summary: Continuous infusion induced more cell toxicity than intermittent infusion, and doses 5 mg/ml increased toxicity Author recommendation: consider intermittent infusion to reduce vein irritation and localized phlebitis N/A SPC was tested for patency and was working appropriately and not running subcutaneously. Vancomycin discontinued and SPC removed; lesion regressed and recovered. Four weeks later, vancomycin administered via central catheter (subclavian) without adverse reaction. Authors conclude that cause of skin necrosis was due to leakage of the IV catheter or capillary leakage, as a generalized or allergic reaction did not occur after later vancomycin administration. Data collec on: Standardized phlebitis scale used Methodology: Three me periods based on amiodarone dilu on: mg/500 ml mg/500 ml 3. back to 900 mg/500 ml) 23-month study period Current prac ce: all drugs given through SPC All amiodarone infusions used 0.2 micron filter N = 61 documented cases of thrombophlebitis: Amiodarone only = 36/339 (10.6%) Vancomycin only = 5/1675 (0.3%) Neither drug = 9/409 (2.2%) Both drugs = 11 (2.7% rate calculated from published data [11/409]; these patients not addressed further in study by authors Amiodarone infusions: 1.8 times more thrombophlebitis in period 1 (10.3%) vs period 2 (5.8%) and 23.2% in period 3 ( con nues ) VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 29

5 TABLE 1 Evidence Table: Peripheral IV Administration of Vancomycin: Studies and Case Reports of Complications ( Continued ) Citation/ Country/Strength of Evidence Neughebauer et al, USA SOE: IV Paquette et al, Canada SOE: V Type of Evidence/ Study Design Case report, narrative literature review Retrospective record review Research Question/ Purpose Sample/Setting Methodology Results/Findings/Comments Case review and literature summary Describe incidence of extravasa on and related factors. 52-year-old woman developed a generalized pruritic blanchable maculopapular rash 12 hours after start of vancomycin. Over next few days, lesions worsened and became hemorrhagic and nonhemorrhagic vesicles; resolution of lesions within 2 days after discontinuing vancomycin Pediatric tertiary care hospital: patients < 18 years Extravasations identified through 3 mechanisms: computerized reporting system for adverse events, pharmacy dispensing records for therapies to treat extravasation, and databases in individual medical programs within institution Time period: January 1, 2006 through August 31, 2008 MEDLINE search revealed 21 reported cases of vancomycin-induced LABD since Data collec on by 1 trained inves gator using medical records and standardized extravasa on report Case report: vancomycin implicated as all other drugs were discontinued while vancomycin continued and lesions continued. Ampicillin had been stopped, then restarted without sequelae. Additionally: morphology and DIF of the skin lesions suggested a clinical diagnosis of LABD. 23(p274) Literature summary: vancomycin-induced LABD: lesions occurred 1-15 days after starting vancomycin; lesions resolved after vancomycin discontinuation in 100% of reports. 42 cases of extravasation identified: 41 were through an SPC Most frequent age ranges for extravasation: 1-12 months = 38%; 1-12 years = 40% Most common location of extravasation: right hand = 29%; left hand = 20%; right foot = 20% 1 case = vancomycin; unknown if this was the sole agent being infused No information about the severity and outcomes of extravasation events Researchers state that some medications and fluids were being co-infused through the same line when the extravasation injury occurred which made it difficult to determine the offending agent. 24(p342) Peyko & Sasson, SOE: V Case report N/A 84-year-old woman; SPC inserted through a 20-gauge catheter in the patient s wrist. IV vancomycin 1 g administered once per day and cefapime 1 g twice per day. On day 2, severe painful blistering surrounding site in right wrist. Over the following week, necrotic tissue developed with ulceration under a black eschar. N/A Evidence of skin necrosis as a result of vancomycin is scant. Successful management of extravasation with cold compresses and silver sulfadiazine 1% topical application once per day. ( con nues ) 30 Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

6 TABLE 1 Evidence Table: Peripheral IV Administration of Vancomycin: Studies and Case Reports of Complications ( Continued ) Citation/ Country/Strength of Evidence Robibaro et al, Austria SOE: IV Roszell and Jones, USA SOE: IV Type of Evidence/ Study Design In vitro study Inves gate whether glycopep de an bio cs (vancomycin and teicoplanin) were toxic to endothelial cells, possibly resul ng in phlebi s. Nonrandomized, prospective, comparative design Research Question/ Purpose Sample/Setting Methodology Results/Findings/Comments Determine if significant differences in complica ons between pa ents with peripheral IVs who received vancomycin vs other an bio cs with a ph less than 4 Human umbilical venous endothelial cells in vitro All adult patients 18 years who required IV antibiotics for more than 24 hours on a surgical unit, academic medical center N = 153 patients, with: Vancomycin = 49 Not vancomycin = 104 Power analysis required 64 patients in each group. Vancomycin group failed to meet power analysis requirements. Commercially available prepara on of vancomycin was dissolved in sterile water and further diluted to 3 concentra ons using 0.9% NaCl. Viability of the endothelial cells was analyzed by measurement of intracellular ATP levels. Data collec on over 6 months: Standardized phlebitis and infiltration tools Number of SPC attempts Time taken to start IV Delayed doses due to SPC venipuncture Current prac ce: all drugs given through SPC Dilution minimally affected the vancomycin ph: 2 mg/ml (ph 4.1), 5 mg/ml (ph 3.8), and 10 mg/ml (ph 3.7). For vancomycin at 2 mg/ml: no change in cell viability at any time period For vancomycin at 5 mg/ml: no change after 20 minutes or 1 hour but a significant change after 2 hours with a decrease in ATP levels, and thus impaired cell viability For vancomycin at 10 mg/ml: significant decreases in ATP levels after all time periods Cell function was also studied: no cellular changes were found for vancomycin at concentrations of 5 mg/ml or 10 mg/ml as compared with controls. Researchers concluded vancomycin is well tolerated if diluted to a final concentration of less than or equal to 2-5 mg/ml. Note: only results for vancomycin abstracted Vancomycin group had a maximum phlebitis score of 1 versus 2 for other antibiotics. Based on ANOVA, there was no significant difference in phlebitis between vancomycin and other antibiotics ( P =.683). Based on linear regression, no significant difference with vancomycin and phlebitis ( P =.733) or interaction effects. Significant findings included repeat insertions with vancomycin ( P =.038), number of attempts with vancomycin ( P =.018), and infiltration ( P =.020). Infiltration scores ranged from 0 to 2 (based on INS Infiltration Scale) and were significantly increased with vancomycin ( P =.026). Vancomycin was only antibiotic with ph of less than 4 (ph = 3.9). 20 Data from Gorski, Hagle, Bierman. Abbreviations: ANOVA, analysis of variance; ATP, adenosine triphosphate; HUVEC, human umbilical vein endothelial cells; DIF, direct immunofluorescence; IgA, immunoglobulin A; IV, intravenous; LABD, bullous dermatosis; N/A, not applicable; NaCl, sodium chloride; PICC, peripherally inserted central catheter; SOE, strength of evidence; SPC, short peripheral catheter; VAD, vascular access device. VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 31

7 TABLE 2 Noncytotoxic Infusates Listed in Systematic Reviews As Vesicants Not Retained on INS Vesicant List Infusate Listed in Le and Patel Listed in Reynolds et al (2014) 4 Listed in Clark et al (2013) 5 (2014) 9 Rationale for Not Retaining on Vesicant List Albumin ; 1 citation No No Single citation where researchers state that some medications and fluids were being co-infused through the same line when the extravasation injury occurred which made it difficult to determine the offending agent. 24(p3) Aminophylline No 1 neonatal citation, rated as lower risk Amphotericin B Intermediate risk; no evidence of permanent harm in pediatric literature Ampicillin 1 citation Lower risk; evidence of harm in pediatric literature Cloxacillin 1 citation Single 1981 citation; unable to retrieve Limited citations; rated as lower risk No Limited citations; mechanism of tissue damage in a single adult report suggested cause as mechanical compression due to increased fluid Single 1981 citation; unable to retrieve Limited citations; rated as lower risk 5 No No Single citation where researchers state that some medications and fluids were being co-infused through the same line when the extravasation injury occurred which made it difficult to determine the offending agent 24(p3) Doxycycline (tetracycline) 2 citations Furosemide Limited citations; rated as lower risk Gentamicin Limited citations; rated as lower risk Immunoglobulin Limited citations; rated as lower risk Lorazepam 1 citation Metronidazole ; single citation; very large extravasation into dorsum of hand (50 ml) Morphine 1 citation (higher risk) Limited citations No references Single pediatric citation Local consensus No Limited citations; rated as lower risk 5 Neonatal citation rated as lower risk No Limited citations; rated as lower risk 5 Lower risk; evidence of harm in pediatric literature No Limited citations; rated as lower risk 5 1 citation (lower risk; evidence of harm in pediatric literature) ; no citation to support Two citations; no evidence of permanent harm in pediatric literature Pediatric citation rated as intermediate risk; no evidence of permanent harm No No Single citation Neonatal citation rated as intermediate risk No Limited citations; no evidence of permanent harm in pediatric literature; morphine is routinely administered subcutaneously in chronic/palliative pain management ( con nues ) 32 Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

8 TABLE 2 Noncytotoxic Infusates Listed in Systematic Reviews As Vesicants Not Retained on INS Vesicant List ( Continued ) Listed in Le and Patel Listed in Reynolds et al (2014) 4 Listed in Clark et al (2013) 5 (2014) 9 Rationale for Not Retaining on Vesicant List Infusate No No Single citation No No Single citation No No Limited citations No ; Limited citations Single pediatric citation No No Single citation Oxacillin 1 citation Penicillin 1 citation Propofol Several citations Sodium thiopental 2 adult citations Sodium valproate 1 citation and vesicant were used with the recognition that infiltrations can also result in severe injury if untreated, causing severe pain or compartment syndrome with the potential to produce permanent nerve injury and complex regional pain syndrome. They provide a discussion about etiology and extravasation risk factors. A list of medications causing extravasation is classified by vasopressors, hyperosmolar and hypoosmolar agents, and acidic and alkaline agents. Loubani and Green performed a systematic review to include all published reports of local tissue injury or extravasation from vasopressor administration given either via a peripheral or a central vascular access device (CVAD). 8 Vasoconstriction is a well-recognized pharmacologic risk factor for extravasation. They identified 85 articles, mainly case reports, including 270 patients; 325 separate events were identified with 318 related to peripheral IV administration and 7 from central IV administration. Additional review articles document the risk for extravasation associated with contrast media The risk for extravasation is greater with iodinated contrast media due to hyperosmolarity, while low osmolarity contrast media is rarely associated with extravasation. 19 The issue of vancomycin and extravasation generates much discussion among infusion nurses, including the TF members. Vancomycin is administered via peripheral and central vascular access devices (VADs). The 2011 Infusion Nursing Standards of Practice stated that an infusate with a ph of less than 5 or greater than 9 was not appropriate for short peripheral or midline catheters. 14 Based on this standard, some organizations administer vancomycin, with a recognized ph of 4, via a central VAD. However, in a recent literature review, it was found that evidence did not support the ph recommendation as a sole indication for central catheter placement, particularly as it applied to the risk for phlebitis. 20 Based on lack of evidence to support the ph limitations and recognition of the relatively complex decision-making guiding VAD choice, it was removed from the 2016 Standards. However, nonphysiologic ph and hyperosmolarity are pharmacologic risk factors that should be assessed in relation to the risk for extravasation. 15 While there is much concern regarding vancomycin extravasation as reported in online forums and discussions, there are limited published reports of vancomycin extravasation Research reports involving larger numbers of patients receiving vancomycin peripherally describe infiltrations, but not extravasations Two in vitro studies suggest several points. First, vancomycin causes damage to endothelial cells, although this is not induced by acidic ph. Second, intermittent infusion causes less cell toxicity than continuous infusions, which are less common in the United States. Last, dilution to a final concentration of less than or equal to 2 to 5 mg/ml reduces risk for cell damage. 29,30 Based on 5 references and no evidence of permanent harm documented in the pediatric literature, Clark and colleagues gave vancomycin a yellow rating, indicative of intermediate risk. 5 Because of the controversies, the TF VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 33

9 has included a separate evidence table summarizing these studies (Table 1). REFINEMENT OF THE LIST Data from these literature reviews were used to further develop the initial list of noncytotoxic medications and solutions. TF members reviewed the list and analyzed the source citations. Medications with limited citations or with questionable or unsubstantiated extravasations were eliminated from the list based on discussion with the TF during conference call meetings. Infusates not retained are listed in Table 2. The TF compiled the final list of vesicants, using a red and yellow color scheme as used by Clark and colleagues, 5 shown in the Appendix. This list includes infusate ph and osmolarity levels for additional reference. It should be noted that while some vesicant infusates possess extreme ph levels (eg, acyclovir, pentobarbital, phenobarbital, phenytoin) or are clearly hyperosmolar (eg, calcium chloride, high dextrose concentrations), many of the vesicants have neither property. Higher-risk infusates were classified as red; this list includes well-recognized vesicants with multiple citations and reports of tissue damage upon extravasation. Intermediate-risk infusates, classified as yellow, were associated with fewer reports of extravasation, but are recognized as vesicants; published drug information and infusate characteristics indicate caution and potential for tissue damage. Based on the literature, the TF concluded that vancomycin should remain on the yellow list. A simple listing of the red and yellow vesicants (without the ph, osmolarity, and specific references) can be found on the INS Web site ( The TF also created a tool outlining extravasation prevention interventions that could be implemented by organizations and clinicians who administer vesicants based on a review of recommendations compiled from a variety of infusion references. This tool also can be found on the INS Web site ( LIMITATIONS This list was established based on literature reviews that primarily included case reports and on drug literature of currently available infusates. Not all case reports are fully analyzed, and it is important to recognize that, more often, extravasation cases are not reported in the formal literature. On review of many of the citations within the systematic reviews, there are numerous citations from the 1960s to the 1980s. In fact, 27% of the citations from Le and Patel s review are from that time period. Such citations may be less relevant as drug manufacturing methods have changed significantly, improving the quality and consistency of injectable medications. CONCLUSION The first step in preventing extravasation is the recognition of vesicant infusates. Each organization should have a list of vesicant infusates and should address extravasation prevention, as well as management, in policies and procedures. This list provides a sound reference for an organization. However, as stated in the Standards, each facility should reach a consensus on which infusates are considered vesicants (and irritants) based on internal formularies. 15 Based on organizational experience and adverse events, the vesicant list may be expanded to include additional infusates not on the INS list. The knowledge and competency of clinicians who administer infusion therapy must be addressed. The pharmacist is a critical member of the health care team and should be consulted when questioning the characteristics of an infusate. This knowledge, along with a thorough patient assessment inclusive of comorbidities, and mitigation of risk factors, will assist the clinician in advocating for the best vascular access given the prescribed therapy. Anticipated duration and frequency of the vesicant medication or solution is certainly an important consideration. As stated in INS Policies and Procedures for Infusion Therapy, 5th edition, VAD selection is a complex decision that requires critical thinking and analysis; the decision is generally not based on a single factor, such as the medication or solution category of vesicant or irritant. 31 Peripheral administration of a short-term infusion in an emergency situation or a small number of intermittent doses may (or may not ) be appropriate given a patient s vascular assessment. For continuous vesicant infusion or frequent vesicant administration, clinicians must advocate for a CVAD. While less common, it must also be recognized that there is a risk for extravasation with CVADs when infusing vesicants. Lastly, it must be recognized that any infusion medication can potentially cause harm; medications must be carefully reviewed for extravasation risks. Organizations are encouraged to collect extravasation data and to report and publish findings in the interest of patient safety. The TF recommends that this list be reevaluated on a regular basis as new data emerge and as new medications are introduced into the market. ACKNOWLEDGMENTS The task force would like to thank the following individuals for their substantive review of this work: Lynn Hadaway, MEd, RN-BC, CRNI ; Mary Hagle, PhD, RN-BC, FAAN; and John Hingl, MBA, RPh. REFERENCES 1. Oncology Nursing Society. Education of the nurse who administers and cares for the individual receiving chemotherapy and biotherapy. Reviewed January Accessed October 11, Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

10 2. Polovich M, Olsen M, LeFebvre K. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 4th ed. Pittsburgh, PA : Oncology Nursing Society ; Esparza D, ed. Oncology Policies and Procedures. Pittsburgh, PA : Oncology Nursing Society ; Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann Pharmacother ; 48 ( 7 ): Clark E, Giambra BK, Hingl L, Doellman D, Tofani B, Johnson N. Reducing risk of harm from extravasation: a 3-tiered evidence-based list of pediatric peripheral intravenous infusates. J Infus Nurs ; 36 ( 1 ): Truven Health Analytics. Trissel s 2 Clinical Pharmaceutics Database (Parenteral Compatibility). IV INDEX. In: Micromedex Accessed March Gahart BL, Nazareno AR Intravenous Medications: A Handbook for Nurses and Health Professionals. 31st ed. St. Louis, MO : Elsevier/ Mosby ; Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care ; 30 ( 3 ): 653. e Reynolds PM, MacLaren R, Mueller SW, Fish DN, Kiser TH. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy ; 34 ( 6 ): Phillips LD, Gorski L. Manual of I.V. Therapeutics: Evidence-Based Practice for Infusion Therapy. 6th ed. Philadelphia, PA : FA Davis Company ; Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R, eds. Infusion Nursing: An Evidence-Based Approach. 3rd ed. St. Louis, MO : Saunders/Elsevier ; Josephson DL. Intravenous Infusion Therapy for Nurses: Principles and Practice. 2nd ed. Clifton Park, NY: Thomson, Delmar ; Registered Nurses Association of Ontario. Nursing best practice guideline: assessment and device selection for vascular access. rnao.ca/sites/rnao-ca/files/assessment_and_device_selection_for_ Vascular_Access.pdf. Published May Accessed October 13, Infusion Nurses Society. Infusion nursing standards of practice. J Infus Nurs ; 34 ( 1 suppl ): S37-S Gorski L, Hadaway L, Hagle M, McGoldrick M, Orr M, Doellman D. Infusion therapy standards of practice. J Infus Nurs ; 39 ( suppl 1 ): S1-S Doellman D, Hadaway L, Bowe-Geddes LA, et al. Infiltration and extravasation: update on prevention and management. J Infus Nurs ; 34 ( 9 ): Rose TA, Choi JW. Intravenous imaging contrast media complications: the basics that every clinician needs to know. Am J Med ;128(9): Nicola R, Shaqdan KW, Aran S, Prabhakar AM, Singh AK, Abujudeh HH. Contrast media extravasation of computed tomography and magnetic resonance imaging: management guidelines for the radiologist. Curr Probl Diagn Radiol ; 45 ( 3 ): American College of Radiology; ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. Version /media/37d84428bf1d4e1b9a3a2918da9e27a3. pdf. Published Accessed November 27, Gorski LA, Hagle M, Bierman S. Intermittently delivered IV medication and ph: reevaluating the evidence. J Infus Nurs ; 38 ( 1 ): Bohm NM, Wong JG. Bullous dermatosis associated with vancomycin extravasation. Am J Med Sci ; 343 ( 2 ): Hoelen DWM, Tjan DHT, Van Vugt R, van der Meer YG, van Zanten ARH. Severe local vancomycin induced skin necrosis. Br J Clin Pharmacol ; 64 ( 4 ): Neughebauer BI, Negron G, Pelton S, Plunkett RW, Beutner EH, Magnussen R. Bullous skin disease: an unusual allergic reaction to vancomycin. Am J Med Sci ; 323 ( 5 ): Pacquette V, McGloin R, Northway T, DeZori P, Singh A, Carr R. Describing intravenous extravasation in children (DIVE Study). Can J Hosp Pharm ; 64 ( 5 ): Peyko P, Sasson E. Vancomycin extravasation: evaluation, treatment, and avoidance of this adverse drug event. Case Rep Intern Med ; 3 ( 3 ): Caparas JV, Hu JP. Safe administration of vancomycin through a novel midline catheter: a randomized, prospective clinical trial. J Vasc Access ; 15 ( 4 ): Mowry JL, Hartman LS. Intravascular thrombophlebitis related to the peripheral infusion of amiodarone and vancomycin. West J Nurs Res ; 33 ( 3 ): Roszell S, Jones C. Intravenous administration issues: a comparison of intravenous insertions and complications in vancomycin versus other antibiotics. J Infus Nurs ; 33 ( 2 ): Robibaro B, Vorbach H, Weigel G, et al. Endothelial cell compatibility of glycopeptide antibiotics for intravenous use. J Antimicrob Chemother ; 41 ( 2 ): Drouet M, Chai F, Barthelemy C, et al. Influence of vancomycin infusion methods on endothelial cell toxicity. Antimicrob Agents Chemother ; 59 ( 2 ): Gorski L, Hadaway L, Hagle M, McGoldrick M, Meyer B, Orr M, eds. Policies and Procedures for Infusion Therapy. 5th ed. Norwood, MA : Infusion Nurses Society ; VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 35

11 APPENDIX Noncytotoxic Vesicant Infusate List Drug Generic Name/INS Rating ANTIMICROBIALS Acyclovir/ YELLOW Drug Trade Name ph 1 Osmolarity Zovirax mg mosm/kg in ml NaCl 0.9% 2 Nafcillin sodium/ YELLOW Nallpen mosm/kg for 3 g mixed in ml NaCl 0.9% Pentamidine isethionate/yellow Pentam At 100 mg/ml in sterile water for injec on and dextrose 5%, the osmolali es are mosm/kg, respec vely Vancomycin hydrochloride/ YELLOW mg/ml was determined to be 249 mosm/kg in dextrose 5% and 291 mosm/kg in NaCl 0.9% VASOPRESSORS/VASOACTIVE Dobutamine hydrochloride/ RED At a concentra on of 5 mg/ ml (manufacturer and diluents unstated), the osmolality was determined to be 361 mosm/ kg by freezing point depression Dopamine hydrochloride/ RED mg/ml (diluent unspecified) was determined to be 277 mosm/kg Additional Comments/Selected Information From Drug Literature Tissue necrosis has occurred following infusion of acyclovir into extravascular ssues (IFU) 3 Permanent cosme c/func onal harm reported in pediatric literature based on single cita on 4 Severe ssue necrosis with sloughing secondary to subcutaneous extravasa on of nafcillin has been reported 7 Permanent cosme c harm reported in pediatric literature 4 Extravasa ons have been reported that, in some instances, proceeded to ulcera on, ssue necrosis, and/or sloughing at the injec on site. While not common, surgical debridement and skin gra ing have been necessary in some of these cases; long-term sequalae have been reported. If extravasa on occurs, the injec on should be discon nued immediately and restarted in another vein. 8 Vancomycin is irrita ng to ssue; pain, tenderness, and necrosis occur with inadvertent administra on 9 No evidence of permanent harm in reported in pediatric literature 4 Phlebi s has occasionally been reported 10 Local inflammatory changes have been described following inadvertent infiltra on Isolated cases of cutaneous necrosis (destruc on of skin ssue) have been reported 10 Extravasa on may cause necrosis and sloughing of surrounding ssue. Large veins of the antecubital fossa are preferred to veins in the dorsum of the hand or ankle. Less suitable infusion sites should be used only if the pa ent s condi on requires immediate a en on. The physician should switch to more suitable sites as rapidly as possible. The infusion site should be con nuously monitored for free flow. 12 Documented as Vesicant in the Following Key References Clark et al, (Red Clark et al, (Yellow Clark et al, (Yellow Also see Table 1: Limited published reports of extravasation injury. Multiple anecdotal reports. Some larger studies without reported extravasation events. Clark et al, (rated all vasopressors as Red) Loubani & Green, Clark et al, rated all vasopressors as Red Loubani & Green, ( con nues ) 36 Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

12 APPENDIX Noncytotoxic Vesicant Infusate List ( Continued ) Drug Generic Name/INS Rating Epinephrine hydrochloride/ RED Drug Trade Name ph 1 Adrenalin chloride Osmolarity mg/mL solu on was determined to have an osmolarity of 348 mosm/kg 2 Additional Comments/Selected Information From Drug Literature Vasoconstric on-induced ssue sloughing can occur. Infusion during cardiac arrest must be administered by CVAD to ensure delivery to systemic circula on and to avoid extravasa on. 1 Documented as Vesicant in the Following Key References Clark et al, (rated all vasopressors as Red) Loubani & Green, Norepinephrine bitartrate/red Levophed Levarterenol Isotonic with sodium chloride Avoid extravasa on into the ssues, as local necrosis might ensue due to the vasoconstric ve ac on of the drug Blanching along the course of the infused vein, some mes without obvious extravasa on, has been a ributed to vasa vasorum constric on with the increased permeability of the vein wall, permi ng some leakage. This will progress on rare occasions to superficial slough, par cularly during infusion into the leg veins in elderly pa ents or in those suffering from oblitera ve vascular disease. 13 Clark et al, (rated all vasopressors as Red) Loubani & Green, Phenylephrine/ RED Neosynephine NR Extravasa on may cause necrosis or sloughing of ssue 14 Clark et al, (rated all vasopressors as Red) Loubani & Green, Vasopressin injection/red Pitressin Pressyn NR Produces intense vasoconstric on Avoid extravasa on; vasoconstric on that may result in severe ssue necrosis and gangrene can occur 1 Clark et al, (rated all vasopressors as Red) Loubani & Green, FLUIDS/ELECTROLYTES Calcium chloride/ RED Calcium chloride 10% solu on 2050 mosm/l (IFU) Necrosis and sloughing will occur with subcutaneous injec on or extravasa on 15 Clark et al, (Red Calcium gluconate/red Calcium gluconate 10% solu- on 276 mosm/kg For intravenous use only. Subcutaneous or intramuscular injec on may cause severe Clark et al, (Red necrosis and sloughing. 16 Dextrose 10%- 12.5%/YELLOW % dextrose 505 mosm/l A vesicant at concentra ons greater than 10%. Avoid extravasa on. Administra on through a central line is required for prolonged infusions of concentra ons over 10%. 1 Clark et al, (Yellow ( con nues ) VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 37

13 APPENDIX Noncytotoxic Vesicant Infusate List ( Continued ) Drug Generic Name/INS Rating Dextrose 12.5%/RED Parenteral nutrition > 900 mosm/red Drug Trade Name ph 1 Osmolarity % containing 250 mg dextrose monohydrate per milliliter; osmolarity (calc.) 1,250 mosm/l 50% containing 500 mg of dextrose monohydrate per milliliter; osmolarity (calc.): 2500 mosm/l 2 Additional Comments/Selected Information From Drug Literature Variable 3 > 950 mosm/kg Central line for osmolarity > 900 mosm according to guidelines from A.S.P.E.N. due to risk for phlebi s 21 Permanent cosme c/func onal harm reported in pediatric literature 4 Documented as Vesicant in the Following Key References Clark et al, (Red Lawson et al, Clark et al, (Red rating using > 950 mosm/l) Boullata et al, Potassium 60 meq/l/yellow Sodium bicarbonate/red meq/100 ml-200 mosm/l 20 meq/100 ml-400 mosm/l 30 meq/100 ml-601 mosm/l 40 meq/100 ml-799 mosm/l 60 meq/l-763 mosm/l Administer intravenously only with a calibrated infusion device at a slow, controlled rate. Because pain associated with peripheral infusion of potassium chloride solu on has been reported, whenever possible, administra on via central route is recommended for thorough dilu on by the blood stream and avoidance of extravasa on NR Inadvertent extravasa on of intravenously administered hypertonic solu ons of sodium bicarbonate have been reported to cause chemical celluli s because of their alkalinity, with ssue necrosis, ulcera on or sloughing at the site of infiltra on. 19 Clark et al, (Yellow/ Red rating depending upon concentration) Clark et al, (Red Sodium chloride 3%/RED OTHER MEDICATIONS/SOLUTIONS Amiodarone/ YELLOW Arginine monochloride/ YELLOW % 308 mosm/l 0.45% 154 mosm/l 3% 839 mom/kg 23.4% is mosm/kg 4.08 Premixed commercial product at 1.5 mg/ml and 1.8 mg/ml is iso-osmo c 23.4% is hypertonic. Must be diluted prior to administra on. Severe local ssue necrosis (if administered extravascularly). Venous thrombosis or phlebi s extending from the site of injec on, extravasa on 20 Clark et al 4 (Red For infusions longer than 1 hour, do not exceed concentra on of 2 mg/ml unless a central line is used mosm/kg 4 Five cases of permanent cosme c harm reported in pediatric literature. 4 Hypertonic solu on. 22 Clark et al, (Yellow) Contrast medianonionic/red mosm 4 Most extravasa ons associated with nonionic iodinated contrast used for computed American College of tomography (CT) procedures 23 Radiology, ( con nues ) 38 Copyright 2017 Infusion Nurses Society Journal of Infusion Nursing

14 APPENDIX Noncytotoxic Vesicant Infusate List ( Continued ) Drug Generic Name/INS Rating Mannitol 20%/ YELLOW Drug Trade Name ph 1 Osmolarity Osmitrol mosm/l-1375 mosm/l (5%-25% concentra on dependent) 2 Additional Comments/Selected Information From Drug Literature Documented as Vesicant in the Following Key References Venous thrombosis, phlebi s extending from the site of injec on Clark et al, 2013 Skin necrosis 24 4 (Red Pentobarbital sodium/yellow Nembutal sodium NR Parenteral solu ons of barbiturates are highly alkaline. Therefore, extreme care should be taken to avoid perivascular extravasa on or intra-arterial injec on. Extravascular injec on may cause local ssue damage with subsequent necrosis; consequences of intra-arterial injec on may vary from transient pain to gangrene of the limb. IV route usually reserved for cri cal situa ons. Avoid extravasa on Any complaint of pain in the limb warrants stopping the infusion 25 Clark et al, (Yellow Phenobarbital sodium/yellow Phenytoin sodium injection/ RED Luminal sodium mg in 50 and 100 ml dextrose 5% is 296 and 289 mosml/kg 100 mg in 50 and 100 ml sodium chloride 0.9% is 325 and 317 mosm/kg Dilantin mg in 50 and 100 ml of sodium chloride 0.9% 336 and 312 mosm/kg, respec vely Parenteral solu ons of barbiturates are highly alkaline. Therefore, extreme care should be taken to avoid perivascular extravasa on or intraarterial injec on. Extravascular injec on may cause local ssue damage with subsequent necrosis; consequences of intra-arterial injec on may vary from transient pain to gangrene of the limb. Any complaint of pain in the limb warrants stopping the injec on. 26 So ssue irrita on and inflamma on has occurred at the site of injec on with and without extravasa ons of intravenous phenytoin Edema, discolora on, and pain distal to the site of injec on (described as purple glove syndrome ) have also been reported. So ssue irrita on may vary from slight tenderness to extensive necrosis, and sloughing. May not develop for several days a er injec on. Although resolu on of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required fasciotomies, skin gra ing, and amputa on. 27 Clark et al, (Yellow Clark et al, (Yellow Promethazine hydrochloride/ RED Phenergan mg/ml was determined to be 291 mosm/kg Injec on can cause severe chemical irrita on and damage to ssues regardless of the route of administra on. Adverse reac ons include burning, pain, thrombophlebi s, ssue necrosis, and gangrene. In some cases, surgical interven on, including fasciotomy, skin gra, and/or amputa on have been required Because of the risks of intravenous injec on, the preferred route of administra on is deep intramuscular. Observe con nuously if given in a peripheral vein. 28 Clark et al, (Yellow ISMP suggests administering through a large-bore vein but prefers use of a central venous catheter 1 Administra on through hand or wrist veins is strongly discouraged Monitor frequently for signs and symptoms of extravasa ons (eg, burning, erythema, pain, palsies, sensory loss, and swelling along IV site) especially along peripheral sites Because of the close proximity of arteries and veins in the areas most commonly used for intravenous injec on, extreme chemical irrita on, severe spasm of distal vessels, and resultant gangrene requiring amputa on are likely under such circumstances 28 Abbreviations: IFU, drug information for use; ISMP, Institute for Medication Practices; NR, not reported. VOLUME 40 NUMBER 1 JANUARY/FEBRUARY 2017 Copyright 2017 Infusion Nurses Society 39