Vancomycin is a widely used IV antibiotic due to its broad-spectrum of activity, bactericidal nature, and low rates of resistance; however, adverse effects (AEs), including nephrotoxicity, are commonly associated with its use.1 The vancomycin therapeutic monitoring guidelines recognize the incidence of nephrotoxicity and suggest strategies for reducing the risk, including area under the curve/mean inhibitory concentration (AUC/MIC) monitoring rather than trough-only monitoring. Vancomycin-associated acute kidney injury (AKI) has been defined as an increase in serum creatinine (SCr) over a 48-hour period of ≥ 0.3 mg/dL or a percentage increase of ≥ 50%, which is consistent with the Acute Kidney Injury Network (AKIN) guidelines.2,3 Vancomycin-associated AKI is a common AE, with its incidence reported in previous studies ranging from 10 to 20%.4,5
The most common crystalloid fluid administered to patients in the United States is 0.9% sodium chloride (NaCl), also known as normal saline (NS), and recent trials have explored its potential to cause AEs.6-8 Balanced crystalloid solutions, such as Plasma-Lyte and lactated Ringer’s solution (LR), contain buffering agents and lower concentrations of sodium and chloride compared with that of NS. Trials in the intensive care unit (ICU) and emergency department, such as the SMART-MED, SMART-SURG, and SALT-ED have reported a significantly lower rate of AKI when using balanced crystalloids compared with NS due to the concentration of sodium and chloride in NS being supraphysiologic to normal serum concentrations.6,7 Alternatively, the SPLIT trial evaluated the use of NS compared with Plasma-Lyte for ICU fluid therapy and did not find a statistically significant difference in AKI.8 Furthermore, some studies have reported increased risk for hyperchloremia when using NS compared with dextrose 5% in water (D5W) or balanced crystalloids, which can result in metabolic acidosis.6,7,9,10 These studies have shown how the choice of fluid can have a large effect on the incidence of AEs; bringing into question whether these effects could be additive when combined with the nephrotoxicity associated with vancomycin.6-9
Vancomycin is physically and chemically stable if diluted in D5W, NS, 5% dextrose in NS, LR, or 5% dextrose in LR.1 It is not known whether the selection of diluent has an effect on nephrotoxicity or other AEs of vancomycin therapy. Furthermore, clinicians may be unaware or unable to specify which diluent to use. There are currently no practice guidelines that favor one diluent over another for vancomycin; however, trials showing higher rates of AKI and hyperchloremia using NS for fluid resuscitation may indicate an increased potential for vancomycin-associated AKI when using NS as a diluent.6,7,9 This study was performed to evaluate whether the type of crystalloid used (D5W vs NS) can influence adverse outcomes for patients. While many factors may contribute to these AEs, the potential to reduce the risk of negative adverse outcomes for hospitalized patients is a significant area of exploration.
The primary outcome of this study was the incidence of AKI, defined using AKIN guidelines where the increase in SCr occurred at least 24 hours after starting vancomycin and within 36 hours of receiving the last vancomycin dose.3 AKI was staged using the AKIN guidelines (stage 1: increase in SCr of ≥ 0.3 mg/dL or by 50 to 99%; stage 2: increase in SCr by 100 to 199%; stage 3: increase in SCr by > 200%) based on changes in SCr from baseline during vancomycin therapy or within 36 hours of stopping vancomycin therapy.3 Secondary outcomes included the incidence of hyperglycemia, hyperchloremia, metabolic acidosis, hypernatremia, mortality in hospital, and mortality within 30 days from hospital discharge.
Methods
This single-center, retrospective study of veterans who received IV vancomycin within the North Florida/South Georgia Veterans Health System (NF/SGVHS) in Gainesville, Florida, from July 1, 2015 to June 30, 2020, compared veterans who received vancomycin diluted in NS with those who received vancomycin diluted in D5W to assess for differences in AEs, including AKI, metabolic acidosis (serum bicarbonate level < 23 mmol/L), hyperchloremia (serum chloride levels > 108 mmol/L), hypernatremia (serum sodium > 145 mmol/L), and hyperglycemia (blood glucose > 180 mg/dL). The endpoint values were defined using the reference ranges determined by the local laboratory. At NF/SGVHS, vancomycin is diluted in D5W or NS based primarily on factors such as product availability and cost.
Study Criteria
Veterans were included if they received IV vancomycin between July 1, 2015 and June 30, 2020. The cohorts were grouped into those receiving vancomycin doses diluted in NS and those receiving vancomycin doses diluted in D5W. Veterans were excluded if they received < 80% of vancomycin doses diluted in their respective fluid, if they were on vancomycin for < 48 hours, or if they did not have laboratory results collected both before and after vancomycin therapy to assess a change. There were more patients receiving vancomycin in D5W, so a random sample was selected to have an equal size comparison group with those receiving NS. A sample size calculation was performed with an anticipated AKI incidence of 14%.5 To detect a 10% difference in the primary outcome with an α of 0.05 and 75% power, 226 patients (113 in each cohort) were needed for inclusion.
Data were collected using the Data Access Request Tracker tool through the US Department of Veterans Affairs (VA) Informatics and Computing Infrastructure. Data collected included demographics, laboratory data at baseline and during vancomycin therapy, characteristics of antibiotic therapy, and mortality data. Of note, all laboratory values assessed in this study were obtained while the veteran was receiving vancomycin or within 36 hours of receiving the last vancomycin dose to appropriately assess any changes.
Statistical analysis of categorical data were analyzed using a χ2 test on the GraphPad online program. This study received institutional review board approval from the University of Florida and was conducted in accordance with protections for human subjects.