January 2015 FAQs
January 2015 FAQs
What is the Evidence for Use of Bronchodilators in Bronchiolitis?
What is the Evidence for Use of Bronchodilators in Bronchiolitis?
Bronchiolitis is a common respiratory disorder in infants that is often caused by viral infections of the lower respiratory tract. 1,2 Bronchiolitis is defined by inflammation of the bronchioles. Characteristic signs and symptoms include rhinitis, tachypnea, wheezing, cough, crackles, use of accessory muscles, and nasal flaring. 2,3
The virus most commonly associated with bronchiolitis is the respiratory syncytial virus (RSV).1 Other associated viruses include the parainfluenza virus, influenza, human metapneumovirus, and adenovirus. Ninety percent of children under the age of 2 years are infected with RSV. This results in lower respiratory infections in as many as 40% of those infected. RSV infection leads to approximately 100,000 hospitalizations annually in children less than 2 years old, with total direct hospital costs of $545 million in 2009. 1,4
Acute viral infection in the upper respiratory tract spreads to the epithelial cells in the lower small airways. 2,3 This results in airway edema, necrotic epithelium, mucus production, and, ultimately, obstructed airflow. Bronchospasm does not play a large role in the pathology of bronchiolitis. Risk factors for severe disease include age less than 12 weeks, prematurity, underlying cardiopulmonary disease, and immunodeficiency. 1
According to the American Academy of Pediatrics (AAP), the mainstay of treatment for bronchiolitis is supportive care, including, hydration, and supplemental oxygen, if needed. 1Pharmacological interventions that have been used include bronchodilators, nebulized hypertonic saline, corticosteroids, and ribavirin; however, with the exception of nebulized hypertonic saline, there is a lack of data showing that routine use of the other options improve the clinical course for bronchiolitis. 1-3,
Bronchodilators are a class of drugs that are used for the treatment of airway disorders, primarily chronic obstructive pulmonary disease (COPD) and asthma. 5,6 Bronchodilators work by relaxing airway smooth muscle tone, leading to reduced respiratory muscle activity and improved ventilation. Beta-adrenergic agonists can have action at both beta-1 and beta-2 receptors. Stimulation of beta-1 adrenergic receptors leads to increased heart rate and increased myocardial contractility and conduction. Beta-2 stimulation causes bronchial dilation, vasodilation, enhancement of mucociliary clearance, and inhibition of the release of mediators from mast cells and basophils. Beta-2 selective agents, such as albuterol, are preferred to provide maximum benefit with the least adverse effects. Although epinephrine is not selective to beta-2 adrenergic receptors, it may offer a potential benefit because of its alpha-adrenergic properties in addition to beta-adrenergic stimulation. 7,8 This results in vasoconstriction, reduced edema, decreased nasal secretions, and pressor effects.
Racemic epinephrine has approval by the Food and Drug Administration (FDA) for the treatment of asthma in adults and children 4 years and older. 9 It is used off-label for croup and bronchiolitis. 10 For croup, a dose of 0.05 mL/kg up to a maximum of 0.5 mL per dose of a 2.25% racemic epinephrine has been used as a nebulizer treatment in infants and children.10Subcutaneous administration of epinephrine is used off-label and has been studied in the pediatric population for treatment of asthma and acute wheezing in infants, such as that found with bronchiolitis. 11 A dose of 0.01 mg/kg (of epinephrine 1 mg/mL) every 15 minutes for 2 doses has been used. 10
Albuterol is also approved for the treatment of asthma in adults and children 4 years and older. 10 The typical dose for exacerbation of asthma is 0.15 mg/kg (minimum dose of 2.5 mg) given as a nebulized solution. Doses may be repeated every 20 minutes for 3 doses and then every 1 to 4 hours as needed. Albuterol may also be administered as an oral tablet, with a dose of 0.1 mg/kg given 3 times daily used for asthma. Similar inhalation and oral dosing strategies have been used in bronchiolitis studies. 12,13
Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. 10 Levalbuterol is the R(-)-enantiomer of racemic albuterol. This isomer is responsible for all of the beta-2 receptor binding and bronchodilating activity. It is theorized that the S(+)-enantiomer, which does not bind to beta-2 receptors, may be responsible for some of the adverse effects of racemic albuterol, including airway hyperreactivity and blunting of albuterol efficacy with prolonged use. Thus, it is postulated that use of levalbuterol may result in decreased adverse effects; however, this hypothesis is controversial. In addition, there is minimal data on the safety and efficacy of levalbuterol in bronchiolitis. 14 Studies comparing epinephrine to albuterol have found similar rates of adverse effects. 7,8
The AAP bronchiolitis guidelines state that bronchodilators should not be used in the management of bronchiolitis. 1 The role of bronchodilators has been the topic of many randomized controlled trials. Several meta-analyses and systematic reviews have concluded that treatment with bronchodilators may result in improved clinical scores in the outpatient setting, but do not affect the time to resolution or length of hospital stay. 7,8,12,13,15,16 A brief summary of the most recent meta-analyses is presented in Table 1. 7,13 An issue that arises when evaluating these trials is that it is difficult to distinguish bronchiolitis from virus-induced wheezing and asthma. In fact, many older studies included patients who had wheezed before and may have had asthma. Patients with asthma typically respond to bronchodilators; thus, their inclusion in these studies may mask the true efficacy of bronchodilators in bronchiolitis.
Table 1. Meta-analyses on the use of bronchodilators in bronchiolitis.
Gadomski 201413 Hartling 20117 Study inclusion criteria Randomized, placebo-controlled trials of bronchodilators for bronchiolitis in infants and children <24 months
Studies of inhaled steroids and epinephrine were not included
Clinically relevant outcomes that assessed signs or symptoms
Randomized controlled trials evaluating the efficacy of epinephrine versus placebo or other active intervention to treat bronchiolitis in infants and children <24 months Number of studies 30 (11 inpatient, 10 outpatient) 19 (9 inpatient, 10 outpatient) Number of patients 1,992 2,256 Interventions
- Bronchodilators (primarily albuterol/salbutamol) vs placebo
- Epinephrine vs placebo, albuterol/salbutamol, or steroid
- Improvement in oxygen saturation as measured by pulse oximetry
- Rate of admission by day 1 and 7 (for outpatients)
- Length of stay (for inpatients)
- Improvement in clinical scores
- Rate of admission (outpatient)
- Length of stay (inpatient)
- Time to resolution of illness
- Change in clinical score, oxygen saturation, respiratory rate, and heart rate
- Return healthcare visits
- Short and long-term adverse effects
Outcomes No improvement in oxygen saturation
(MD -0.43, 95% CI -0.92 to 0.06)
Statistically significant improvement in overall clinical score (SMD ‑0.30, 95% CI -0.54 to -0.05) but not considered clinically significant
Modest improvement in clinical score with bronchodilators in outpatients (SMD -0.42, 95% CI -0.79 to -0.06)
No reduction in rate of hospitalization, length of stay, or resolution of illness
Epinephrine reduced admissions for outpatients at Day 1 (RR 0.67, 95% CI 0.50 to 0.89) but not at Day 7 (RR 0.81, 95% CI 0.63 to 1.03) vs placebo
No difference in admissions for outpatients at 1 or 7 days with epinephrine vs albuterol/salbutamol or vs steroids
Epinephrine plus steroids reduced admission for outpatients at Day 7 (RR 0.64, 95% CI 0.44 to 0.95) vs placebo but not at Day 1
Inpatient epinephrine group had shorter length of stay compared to albuterol (MD -0.28, 95% CI -0.46 to ‑0.09)
No difference was seen in return visits between epinephrine and albuterol
Clinical scores also favored epinephrine for inpatients in comparison to albuterol at 60 and 120 minutes as did oxygen saturation at 60 minutes
No difference was seen in oxygen saturation, respiratory rate, or return visits between epinephrine and placebo
Adverse effects Tachycardia, decreased oxygen saturation, flushing, hyperactivity, prolonged cough, tremor Adverse events were comparable between active treatments Conclusions Bronchodilators are not effective in the routine management of bronchiolitis.
Analysis limited by small sample sizes and lack of standardized study design and outcomes.
Epinephrine was superior to placebo for short-term outcomes in outpatients within the first 24 hours of care.
Analysis limited by quality of available studies and timing of measurements.
Abbreviations: CI=confidence interval; MD=mean difference; PFTs=pulmonary function tests; RR=relative risk; SMD=standardized mean difference.
There is little benefit from the use of bronchodilators in the treatment of bronchiolitis. Meta-analyses have found that bronchodilator administration has no effect on improvement in oxygen saturation, length of hospitalization, or time to resolution of illness. 7,13 A minimal benefit has been seen in the outpatient setting within the first 24 hours of administration. 7This short-term benefit must be weighed against the costs of these agents and the associated adverse effects, including tachycardia, tremor, and palpitations.
The AAP recommends supportive care for the treatment of bronchiolitis and against the routine use of bronchodilators. 1 Bronchiolitis may often present with symptoms similar to asthma, which is responsive to bronchodilators due to the underlying pathology of inflammation, bronchospasm, and airway hyperreactivity. The pathophysiology of bronchiolitis, on the other hand, involves airway obstruction and plugging, making it less responsive to bronchodilator administration. Although the previous AAP guideline suggested a monitored trial of bronchodilator therapy in patients with bronchiolitis, the 2014 guideline does not support this option due to the more recent evidence demonstrating a lack of benefit with bronchodilators.
1. Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guideline: diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014;134(5):e1474-1502.
2. Zorc JJ. Bronchiolitis trial and tribulation. Acad Emerg Med. 2008;15(4):375-376.
3. Zorc JJ, Hall CB. Bronchiolitis: Recent evidence on diagnosis and management. Pediatrics. 2010;125(2):342-349.
4. Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo CA. Trends in bronchiolitis hospitalizations in the united states, 2000-2009. Pediatrics. 2013;132(1):28-36.
5. Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012;64(3):450-504.
6. Cazzola M, Matera MG. Bronchodilators: Current and future. Clin Chest Med. 2014;35(1):191-201.
7. Hartling L, Bialy LM, Vandermeer B, et al. Epinephrine for bronchiolitis. Cochrane Database Syst Rev. 2011(6):CD003123.
8. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. Epinephrine for bronchiolitis.Cochrane Database Syst Rev. 2004(1):CD003123.
9. Asthmanefrin [package insert]. Orlando, FL: Nephron Pharmaceuticals Corporation; 2013.
10. Micromedex healthcare series [database online]. http://micromedexsolutions.com/. Updated 2013. Accessed August 15, 2014.
11. Lowell DI, Lister G, Von Koss H, McCarthy P. Wheezing in infants: The response to epinephrine. Pediatrics. 1987;79(6):939-945.
12. Gadomski AM, Brower M. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2010(12):CD001266.
13. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014(6):CD001266.
14. Levin DL, Garg A, Hall LJ, Slogic S, Jarvis JD, Leiter JC. A prospective randomized controlled blinded study of three bronchodilators in infants with respiratory syncytial virus bronchiolitis on mechanical ventilation. Pediatr Crit Care Med. 2008;9(6):598-604. doi: 10.1097/PCC.0b013e31818c82b4 [doi].
15. King VJ, Viswanathan M, Bordley WC, et al. Pharmacologic treatment of bronchiolitis in infants and children: A systematic review. Arch Pediatr Adolesc Med. 2004;158(2):127-137.
16. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. A meta-analysis of randomized controlled trials evaluating the efficacy of epinephrine for the treatment of acute viral bronchiolitis. Arch Pediatr Adolesc Med. 2003;157(10):957-964.
Bridget Hoy, PharmD
College of Pharmacy
University of Illinois at Chicago
What are Current Recommendations for Treatment of Drug Extravasation?
What are Current Recommendations for Treatment of Drug Extravasation?
Extravasation is defined as the leakage or inadvertent administration of a vesicant drug or solution from a vein into the extravascular space.1 Infiltration, often used in reference to extravasation, refers to leakage of a drug or solution classified as an irritant.2,3 Initial symptoms of extravasation are similar to infiltration and include persistent pain, burning, stinging, swelling, and either blanching or erythema at the site of injection or along the course of the vein. However, vesicants are differentiated from irritants in that they can cause tissue necrosis, blistering, and ulceration. Damage from extravasation can progress to a significant enough extent to cause permanent disability and disfigurement, and necessitate surgical debridement or skin grafting.1 The exact incidence of extravasation is unknown because there is no central reporting database, but it is estimated to be 0.1-6% for nonvesicant drugs in adults, and up to 11% for nonvesicants in pediatrics.1 For vesicant drugs and chemotherapeutic agents, the incidence ranges from 0.01-6%.2
Risk factors for extravasation
There are a variety of risk factors associated with extravasation: mechanical (cannulation technique), patient-related (predisposition to infiltration injury), and pharmacologic (pH, osmolality, vasoactivity, and cytotoxicity of infusate).1,2,4 Drugs with an extremely low or high pH (defined as pH less than 5 or greater than 9) irritate the veins, leading to an inflammatory response of the endothelial cells, which enables drug to leak out of the vein. Osmolality is also a consideration, as differences in osmotic pressure can damage endothelial cells, leading to potential for drug leakage from vessels. Certain drugs can also cause vasospasms, which cause back pressure at the intravenous (IV) site and can expand the puncture site in the vein, allowing leakage to occur. Drugs that act as vasoconstrictors can cause tissue ischemia. Some drugs, including anti-cancer agents are directly cytotoxic to cells.4 Cytotoxic agents can be further subdivided into DNA binding and non-DNA binding agents. Additionally, administration factors, including the experience of personnel administering the injection, the injection technique, and the number of venipuncture attempts to establish a line contribute to the risk of extravasation, as does the fragility of the patient’s veins.1,2,4
Interventions for extravasation
The best approach to extravasation injury is prevention.3,5 Preventive measures, such as appropriate dilution of medication, infusion of medication via the appropriate rate of administration, careful monitoring of infusions as they are being administered, use of clear tape or dressings to allow for visual inspection of the infusion site, and immobilization of the extremity with the IV cannula are all possible means to prevent extravasation and its serious outcomes.
Non-pharmacologic interventions for extravasation
For most medications, the treatment of extravasation is nonpharmacologic in nature; however, the efficacy of any specific approach has not been demonstrated in controlled studies.3 The recommended approach to the treatment of extravasation includes the following steps:1,3-5
1. Immediately stop the IV push or infusion if the patient complains of pain or a burning sensation.
2. Disconnect IV tubing from IV device. Do not remove the IV device or noncoring port needle.
3. Leave the catheter or needle in place initially to attempt to aspirate fluid from the extravasated area. Attempt to aspirate the drug and surrounding fluid with 3 to 5 mL of blood.
4. Remove the peripheral IV device or port needle.
5. Assess the site of extravasation and the symptoms of the patient.
6. Notify the physician.
7. Elevate the affected limb to minimize swelling and encourage resorption of the drug via the lymphatic system.
8. Apply warm or cold compresses as indicated depending on the drug extravasated.
- Generally cold compresses are recommended for extravasation of all irritant and vesicant drugs except vinca alkaloids (vincristine, vinblastine, vinorelbine), epipodophyllotoxins (etoposide), oxaliplatin, and vasopressors, as cold worsens tissue ulceration caused by these drugs. Cold compresses cause vasoconstriction, limiting the spread of the extravasated drug. Additionally, cold reduces local inflammation and pain.
- Apply for 20 minutes 3 or 4 times daily for the first 24 to 48 hours after extravasation occurs.
- Hot compresses are preferred for extravasation of specific drugs including vinca alkaloids, vasopressors, and oxaliplatin to increase local blood flow and enhance drug removal.
9. Consider debridement and excision of necrotic tissue if pain continues for 1 to 2 weeks.
Pharmacologic interventions for extravasation
For some medications, nonpharmacologic management of extravasation is insufficient based on clinical presentation, and specific pharmacologic antidotes are used. The goal of antidote administration is to reverse the action of the extravasated agent, interfere with the process of cell destruction, prevent tissue necrosis, or limit the extent of tissue damage.4,5 The efficacy of antidotes has been evaluated primarily from animal studies or reported anecdotally based on human experience; therefore, their true efficacy is unknown.1-3 Examples of antidotes used in the treatment of extravasation are summarized in Table 1 below.
Table 1. Specific antidotes for extravasation. 1,2,4-7
Antidote Preparation A d ministration Dexrazoxanea MOA: Unknown, may reversibly inhibit topoisomerase II thereby protecting tissue from anthracycline cytotoxicity Used for anthracycline extravasation
- Each vial of dexrazoxane 500 mg must be mixed with 50 mL diluent to a concentration of 10 mg/mL
- Dilute reconstituted solution in lactated Ringer, NS, or D5W to a final concentration of 1.3 to 5 mg/mL depending on specific manufacturer instructions
- Withhold cold pack 15 minutes prior to infusion
- Begin infusion as soon as possible and within 6 hours of anthracycline extravasation
- Dose is based on patient’s body surface area
- Day 1: 1000 mg/m2(max dose 2000 mg)
- Day 2: 1000 mg/m2(max dose 2000 mg)
- Day 3: 500 mg/m2(max dose 1000 mg)
- Treatment of day 2 and day 3 should start at the same hour (± 3 hours) as on day 1
- Reduce dose by 50% in patients with creatinine clearance < 40 mL/min
- Administer over 1 to 2 hours in a large vein in an area remote from the extravasation
- DMSO should not be used as it may diminish dexrazoxane efficacy
Hyaluronidase MOA: promotes diffusion of SC injection solutions by hydrolyzing hyaluronic acid in connective tissue, possibly creating a wider surface area for dilution and aspiration of extravasated drug Used for etoposide, vinca alkaloids, taxanes, hyperosmolar agents, hypoosmolar agents, agents containing propylene glycol, acidic, and alkaline agents
- Vial contains 150 units per 1 mL or 200 units per 1 mL depending on manufacturer
- To obtain a 15 unit/mL concentration, mix 0.1 mL (of 150 units/mL) with 0.9 mL normal saline in 1 mL syringe
- For extravasation of hyperosmolar solutions: 15 to 25 units intradermally over 5 injections
- For extravasation of acidic/ basic agents : 15 units intradermally along injection site and edematous area
- Inject from 15 to 150 units of the hyaluronidase solution as 5 separate injections, each containing 0.2 mL to 1 mL of hyaluronidase
- Use a 25-gauge needle to affected area (change needle with each injection)
Sodium ThiosulfateMOA: neutralizes reactive species and reduces formation of hydroxyl radicals that can cause tissue injury Used for cisplatin, cyclophosphamide, mechlorethamine, alternative for hyperosmolar agents
- Prepare 1/6 molar solution:
- From 25% sodium thiosulfate solution: mix 1.6 mL with 8.4 mL sterile water for injection
- From 10% sodium thiosulfate solution: mix 4 mL with 6 mL sterile water for injection
- Hyperosmolar extravasations (severe): 12.5 g IV over 30 min
- Use 2 mL of the prepared solution for each 1 mg drug extravasated
- Inject SC using a 25-gauge needle to affected area
- Hyperosmolar extravasations (severe): may increase to 25 g 3 times/ week
DMSO MOA: scavenges free radicals and has anti-inflammatory, analgesic, and vasodilatory effects which promote systemic absorption of drug Used for mitomycin, dactinomycin, mitoxantrone and possible alternative for anthracyclines
- 50% solution (99% solution reported in literature, but not available in US)
- Apply topically to site for 7 – 14 days
Phentolamine MOA: α-adrenergic antagonist that promotes vasodilation and capillary blood flow Used for vasopressors
- 5 to 10 mg in 10 to 20 mL NS
- 0.5 to 4.5 mg in 5 mL NS for epinephrine autojector-induced ischemia
- Inject at multiple sites across symptomatic areas · Longest reported time in literature with effective treatment is 13 hours
Nitroglycerin pasteMOA: increases nitric oxide, promoting vasodilation Used for vasopressors (alternative to phentolamine), hyperosmolar agents
- 2% paste
- 5mg/day transdermal patch
- 1-inch strip applied to site of ischemia, can redose every 8 hours as necessary
- 1 patch daily
Terbutaline MOA: α-adrenergic antagonist that promotes vasodilation and capillary blood flow Used for vasopressors (alternative to phentolamine)
- 1 mg in 10 mL NS
- Inject locally across symptomatic sites
DMSO=dimethyl sulfoxide; D5W=dextrose 5% water; IV=intravenous; MOA=mechanism of action; NS=normal saline; SC=subcutaneous. a Dexrazoxane on shortage at the time this document was written
Management of Extravasation of Cytotoxic Drugs
Management of extravasation of cytotoxic drugs consists of immediate application of either a cold or hot compress depending on the drug and administration of an antidote when available. Treatment is outlined in Table 2 below.
Table 2. Pharmacologic Therapy for Extravasation of Cytotoxic Drugs.3,4,7,8
Medication Extravasated Immediate Topical Therapy Antidote Cisplatin > 0.4mg/mL Apply ice pack for 15 to 20 min at least 4 times daily for the first 24 to 48 h Sodium thiosulfate Cyclophosphamide Apply ice pack for 15 to 20 min at least 4 times daily for the first 24 to 48 h Sodium thiosulfate Daunorubicin Doxorubicin Epirubicin Idarubicin Apply ice pack (but remove at least 15 min prior to dexrazoxane) Dexrazoxanea Etoposide Apply warm dry pack Hyaluronidase Mechlorethamine Apply ice packs for 6 to 12 h following thiosulfate antidote injection Sodium thiosulfate Mitomycin Dactinomycin Mitoxantrone Apply ice packs for 15 to 20 min at least 4 times/day for the first 24 h Topical DMSO Vinblastine Vincristine Vinorelbine Elevate extremity and apply dry warm pack for 15 to 20 min at least 4 times daily for the first 24 to 48 h Hyaluronidase Oxaliplatin Apply warm packs (Ice increases risk of cold-induced peripheral neuropathy) Dexamethasone 8 mg twice daily for 14 days Docetaxel Paclitaxel Nab-paclitaxel Apply ice pack for 15 to 20 min at least 4 times daily for the first 24 h Hyaluronidase
a DMSO may be an option when dexrazoxane is not available; however, it should not be used once dexrazoxane has been given.3,8 DMSO=dimethyl sulfoxide.
Management of extravasation of non-cytotoxic drugs
The management of non-cytotoxic drugs is largely supportive and non-pharmacological, except where antidotes exist, such as for vasopressors. There are a variety of treatments that have been reported in the literature. Treatment considerations are outlined in Table 3 below.
Table 3. Extravasation of non-cytotoxic drugs.1,2
Medication Immediate topical therapy Antidote/ Treatment Considerations VasopressorsNorepinephrine Epinephrine Dopamine Dobutamine Methylene blue Vasopressin Phenylephrine Consider use of warm compress Preferred : Phentolamine for most agents; topical nitroglycerin for vasopressin and methylene blueAlternative: Topical nitroglycerin paste, terbutaline Hyperosmolar agents Total parenteral nutrition Calcium chloride 10% Calcium gluconate Dextrose 10% to 50% Mannitol 20% Hypertonic saline Potassium 60 mEq/L Arginine Ampicillin Sodium bicarbonate 8.4% Radiographic contrast media Consider use of warm or cold compress Preferred : HyaluronidaseAlternative for calcium :Sodium thiosulfate Alternative for total parenteral nutrition : topical nitroglycerin paste Hypo-osmolar agentsAminophylline Nafcillin Consider use of warm or cold compress Hyaluronidase Substances containing propylene glycol Etomidate Lorazepam Diazepam Nitroglycerin Digoxin Phenytoin Phenobarbital Consider use of warm or cold compress Hyaluronidase Acidic and alkaline agentsPhenytoin Acyclovir Promethazine Sodium thiopental Vancomycin Doxycycline Conivaptan Amiodarone Pentamidine Dry heat and elevation Hyaluronidase
Extravasation is a potentially serious unintended event associated with IV drug administration. Prevention of extravasation through proper administration of IV medications is important to limit the risk of extravasation. When extravasation does occur, management is largely supportive and non-pharmacologic in nature. Evidence supporting the use of specific antidotes is limited and largely limited to case reports.
1. Reynolds P, MacLaren R, Mueller S, et al. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014;34(6):617-632.
2. Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann of Pharmacother. 2014;48(7):870-876.
3. Pérez Fidalgo JA, Garcia Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-ENOS Clinical Practice Guidelines . Ann Oncol. 2012; 23(7)(suppl 7):vii167-vii173.
4. Schulmeister L. Infusion-related complications. In: Polovich M, Olsen M, Lebvre K, eds.Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 4th ed. Pittsburgh, PA: Oncology Nursing Society; 2014.
5. Payne AS, Savarese DMF. Extravasation injury from chemotherapy and other non-antineoplastic vesicants. In: Post TW, ed. UpToDate. Waltham, MA: Wolters Kluwer Health, 2014. http://www.uptodate.com. Accessed November 1, 2014.
6. Lexicomp [database online]. Hudson, OH: Wolters Kluwer Health; 2014. http://onlinelexi.com. Accessed November 6, 2014.
7. Poisindex [database online]. Greenwood Village, CO: Truven Health Analytics; 2014. http://www.micromedexsolutions.com. Accessed November 6, 2014.
8. Wang R. Extravasation of xenobiotics. In: Nelson L, Lewin N, Howland M, Hoffman R, Goldfrank L, Flomenbaum N, eds. Goldfrank’s Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011. http://accessemergencymedicine.mhmedical.com/content.aspx?bookid=454§ionid=40199442&jumpsectionID=40215299&Resultclick=2. Accessed November 7, 2014.
Jennifer Anderson, PharmD
College of Pharmacy
University of Illinois at Chicago
Is Vancomycin Therapy with Targeted Troughs Between 15 and 20 mg/L Associated with an Increased Risk of Nephrotoxicity?
Is Vancomycin Therapy with Targeted Troughs Between 15 and 20 mg/L Associated with an Increased Risk of Nephrotoxicity?
In 1952, a compound produced by Streptomyces orientalis that was active against penicillin-resistant staphylococci was isolated.1-3 This formulation was approved by the US Food and Drug Administration (FDA) in 1958 as vancomycin. Original formulations were only 70% pure and referred to as “Mississippi Mud” because of its brown color.1-4 The nephrotoxicity seen with older formulations was attributed to these impurities, and therapy with vancomycin became second-line with the introduction of safer beta-lactams that entered the market around the same time. The purity of vancomycin preparations increased to 95% in 1985, and animal studies reported reduced toxicities, including nephrotoxicity, with these improved formulations. With the emergence of methicillin resistant Staphylococcus aureus (MRSA), the use of vancomycin has exploded since the 1980s, and vancomycin remains the treatment of choice for empiric gram-positive infections and MRSA infections.
Consensus guideline dosing recommendations
The pharmacokinetic properties of vancomycin are defined by the area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio.5,6 An AUC/MIC ≥400 is associated with clinical efficacy in the treatment of MRSA with an MIC <1. Prior to 2005, 1000 mg every 12 hours was the standard recommended dose of vancomycin for all patients.2 However, this dose failed to reach the target AUC/MIC in most patients, and in 2005, the Infectious Diseases Society of America (IDSA) recommended targeted dosing of vancomycin with goal troughs between 15 and 20 mg/L for the treatment of pneumonia.2,7 In 2009, this targeted dosing was expanded to other serious gram-positive infections, including bacteremia, endocarditis, osteomyelitis, and meningitis.4 In recent years, increasing doses of vancomycin have been used to overcome increasing MICs and to reach hard to penetrate tissues.8 As a result, there have been increasing reports of vancomycin-associated nephrotoxicity (VAN), and this remains a heavily debated topic.
The reported incidence of VAN ranges from 1% to 43% in the literature.2,3,8,9 This large incidence range is the result of differences in the populations studied, other risk factors for development of nephrotoxicity, and different definitions of VAN used. VAN is thought to result from overall exposure to vancomycin, including increased trough concentrations and longer durations of therapy, a myriad of host-related factors, and/or the concomitant administration of other nephrotoxic medications.
In the studies that evaluated VAN, an array of definitions makes it more difficult to draw firm conclusions about the association between vancomycin and nephrotoxicity when comparing studies. The following Table discusses the common definitions used within the literature.
Table. Common definitions of vancomycin-associated nephrotoxicity.2-4
Standard Definition4 At least 2 or 3 consecutive serum creatinine concentrations (increase of 0.5 mg/dL or ≥50% increase from baseline, whichever is greater) after several days of therapy in the absence of an alternative explanation RIFLE2 Serum Creatinine Urine Output GFR Risk Increase 50% above baseline <0.5 mL/kg/h for 6 h Decrease by >25% Injury 2x baseline <0.5 mL/kg/h for 12 h Decrease by >50% Failure 3x baseline or ≥4 mg/dL with acute increase of ≥0.5 mg/dL <0.3 mL/kg/h for 24 h or anuria for 12 h Decrease by ≥75% Loss Persistent failure with complete loss of function for >4 wks End (ESRD) Failure lasting >3 mo AKIN2 Serum Creatinine Urine Output Stage I Increase of ≥0.3 mg/dL or ≥50% above baseline within 48 h Decrease to <0.5 mL/kg/h for >6 h Stage II 2x baseline Decrease to <0.5 mL/kg/h for >12 h Stage II 3x baseline or ≥4 mg/dL with acute increase of ≥0.5 mg/dL Decrease to <0.3 mL/kg/h for 24 h or anuria for 12 h Abbreviations: AKIN, acute kidney injury network; ESRD, end-stage renal disease; RIFLE: risk, injury, failure, loss, end state.
Proposed mechanism of nephrotoxicity
Although current formulations of vancomycin are purified, some generic formulations still contain fermentation and degradation by-products, including crystalline degradation product (CDP) and CDP-1, which can increase the risk of nephrotoxicity.2 The exact mechanism of nephrotoxicity of vancomycin is unknown, but several mechanisms have been proposed.2-4, 9,10 Vancomycin is thought to affect the proximal tubule, loop of Henle, and the collecting duct. In the proximal tubule, an accumulation of vancomycin results in an increased proliferation of epithelial cells, stimulation of oxidative phosphorylation, formation of oxygen radicals, and complement mediated inflammation. Oxidative stress leads to tubular ischemia, tubulointerstitial damage, and destruction of glomeruli. For the majority of patients, VAN appears to reversible, resulting in 3% of patients requiring short-term dialysis.3,10
Impact of VAN
Drug-induced nephrotoxicity and acute kidney injury (AKI) are very costly events, as a result of increased length of stay (LOS) and increased laboratory costs (e.g., serum creatinine concentrations, vancomycin trough concentrations).2 VAN, specifically, has been associated with increased LOS, increased mortality, and the need for dialysis.3 At this time, it is unclear if there are other outcomes specific for VAN that are different from outcomes associated with other drug-induced nephrotoxicity.
A systematic review and meta-analysis evaluated published literature on VAN from January 1995 to April 2012.11 Studies were included if the risk of VAN was stratified by vancomycin troughs (<15 mg/L and ≥15 mg/L). Two hundred forty studies were reviewed, and 15 were included in the meta-analysis. Troughs were drawn after steady state was achieved, but not greater than 4 days after therapy. Six studies evaluated the average vancomycin trough, while 8 studies evaluated the initial vancomycin trough. In patients with multiple vancomycin troughs throughout treatment, the highest value was used for analysis. Twelve studies used the standard definition of nephrotoxicity as listed in the Table above, one used AKIN, one used RIFLE, and one used a different definition.
Similar to the reported literature, the incidence of nephrotoxicity varied from 5% to 43% and occurred between 4.3 and 17 days after initiation of vancomycin.11 Troughs ≥15 mg/L were associated with increased nephrotoxicity (odds ratio [OR] 2.67; 95% confidence interval [CI] 1.95 to 3.65; p<0.01). Four studies associated an increased exposure to vancomycin as contributing to VAN, and the highest rates of nephrotoxicity were observed in patients with troughs >20 mg/L. In addition, duration of therapy greater than 7 days was associated with an increased risk of VAN. Although not consistent throughout all of the studies, patients in the intensive care unit (ICU) (OR 2.57; 95% CI 1.44 to 4.58; p<0.01) and patients receiving concomitant nephrotoxins (OR 3.30; 95% CI 1.30 to 8.39; p=0.01) were at an increased risk of developing VAN. In 5 studies, vancomycin troughs >15 mg/L were an independent risk factor for VAN. In patients who experienced VAN, the majority of patients returned to baseline serum creatinine and most episodes of VAN resolved within 1 week. The authors concluded that that these results strongly suggest an association between VAN and troughs ≥15 mg/L.
Other risk factors for VAN
In addition to increased trough concentrations, several other risk factors have been associated with VAN. These include vancomycin-exposure related factors, host factors, and use of concurrent nephrotoxic agents.2,3 Vancomycin-exposure risk factors include accumulation of drug with prolonged duration of therapy greater than 6 to 14 days and total daily doses greater than 4 g per day. Host factors include obesity (weight >100 kg), preexisting renal dysfunction or history of an AKI, critical illness or ICU admission, type of infection, and African American ethnicity. Finally, the presence of other nephrotoxic agents, including aminoglycosides, loop diuretics, vasopressors, contrast dye, and amphotericin B, have been associated with an increased risk of VAN. In 3 recent retrospective reviews, the combination of vancomycin and piperacillin-tazobactam was associated with an increased risk of VAN. 7-9
In 125 patients who received greater than 72 hours of therapy with vancomycin and were admitted to an internal medicine service, a multivariate analysis found a significant association between VAN and acute hypotensive events, baseline creatinine clearance, Charlson comorbidity index, and concomitant use of piperacillin-tazobactam.8 This study reported a cumulative incidence for VAN of 13.6%. Concurrent use of piperacillin-tazobactam was associated with a >5-fold increased odds of VAN (OR 5.36; 95% CI 1.41 to 20.5) versus no concurrent use. In 191 patients, nephrotoxicity was observed in 8.08% of patients on vancomycin monotherapy versus 16.3% of patients on vancomycin and piperacillin-tazobactam (p=0.041).9 An estimated or measured vancomycin trough concentration >15 mg/L was associated with an increased risk of nephrotoxicity (OR 3.67; 95% CI 1.49 to 9.03).9In 224 patients, the incidence of nephrotoxicity was significantly higher in patients who received vancomycin and piperacillin-tazobactam concurrently as compared to vancomycin and cefepime for at least 48 hours (OR 3.74; 95% CI 1.89 to 7.39; p<0.0001).10 There was no significant difference in high initial vancomycin troughs.
The consensus statement from American System of Health-System Pharmacists, IDSA, and the Society of Infectious Diseases Pharmacists in 2009 states that there is not enough published data to support a causal relationship between vancomycin and nephrotoxicity.4 In 2012, a meta-analysis published by van Hal and colleagues found a strong association between vancomycin trough concentrations ≥15 mg/L and nephrotoxicity.11 In addition to elevated trough concentrations, there are several risk factors that have also been associated with an increased risk of VAN, including overall vancomycin exposure, host-related factors, and concomitant administration of other nephrotoxic medications.
In regards to published literature, data are often conflicting and confounding variables are present. Additionally, information regarding confounding variables is often unknown, making it more difficult to make a direct association between vancomycin and nephrotoxicity. An increased vancomycin trough concentration and/or concurrent use of piperacillin-tazobactam may place a patient at increased risk of nephrotoxicity, especially if other risk factors are present. Clinicians should be aware of risk factors mentioned above and be more aggressive in monitoring vancomycin trough concentrations and making prompt dose adjustments when appropriate.
1. Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42 (Suppl 1):S5-12.
2. Mergenhagen KA, Borton AR. Vancomycin nephrotoxicity: a review. J Pharm Practice.2014 Sep 28. [Epub ahead of print].
3. Carreno JJ, Kenney RM, Lomaestro B. Vancomycin-associated renal dysfunction: where are we now? Pharmacotherapy. 2014;34(12):1259-1268.
4. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.Am J Health Syst Pharm. 2009;66(1):82-98.
5. Moise PA, Forrest A, Bhavnani SM, et al. Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus. Am J Health Syst Pharm. 2000;57(Suppl 2):S4-9.
6. Holmes NE, Turnidge JD, Munckhof WJ, et al. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2013;57(4):1654-1663.
7. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.
8. Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy. 2014;34(7):653-661.
9. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam.Pharmacotherapy.2014;34(7):670-676.
10. Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime.Pharmacotherapy. 2014;34(4):662-669.
11. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-744.
Cassie Stromayer, PharmD
College of Pharmacy
University of Illinois at Chicago