December 2018 FAQs

Does administration of sodium bicarbonate to patients with severe metabolic acidosis yield a mortality benefit?

Background

Metabolic acidosis is associated with multiple physiological derangements of the respiratory, cardiac, and nervous systems, including increased ventilation and tidal volume, decreased cardiac contractility, headache, lethargy, and stupor.1,2 Changes in laboratory acid-base markers include decreases in serum pH, sodium bicarbonate (NaHCO3), and partial pressure of carbon dioxide (PaCO2). Theoretically, the administration of NaHCO3 can correct acidosis by providing a weak base.1 However, the use of alkali therapy in patients with acidosis secondary to accumulation of organic acid anions (ie, ketoacidosis or lactic acidosis) is controversial, especially in non-severe cases (pH ≥7.2). Paradoxically, exogenous administration of NaHCO3 may exacerbate acidosis by depressing cardiac contractility and further stimulating lactate production; NaHCO3 may also lead to other unwanted effects, including, hypercapnia, hypokalemia, ionized hypocalcemia, fluid overload, and QTc interval prolongation 1,2

Standards of care and evolving data

Definitive therapy for metabolic acidosis involves identifying and treating the underlying cause of the acid-base imbalance.1-3 Infusions of NaHCO3 are generally reserved for patients with severe metabolic acidosis (pH < 7.2) with a goal of increasing serum pH to ∼7.20 and serum NaHCO3 to ~ 12 mmol/L.1 However, while NaHCO3 infusions provide some improvement in laboratory markers of acid-base status, improvements in clinical outcomes with therapy are less certain. According to the 2016 Surviving Sepsis Campaign guideline, NaHCO3 should not be used to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia associated with sepsis and pH ≥ 7.15.3 Two small randomized-controlled trials comparing infusions of NaHCO3 to sodium chloride on hemodynamics and laboratory parameters of acid-base status provide evidence supporting this recommendation; lower quality evidence in the form of laboratory studies and animal models is also cited by the guideline.3-5 More importantly, during the development phase of this guideline, there were no published studies examining the effects of NaHCO3 infusions on clinical outcomes in patients with metabolic acidosis.3 However, an updated search of literature in PubMed (data since July 2016) identified 2 relevant clinical trials.6,7   

Table 1 summarizes mortality outcomes with NaHCO3 infusion in patients with metabolic acidosis. Infusions of NaHCO3 do not appear to reduce mortality in the general population of patients with metabolic acidosis.6,7 However, in a subgroup of patients with stage 2 or 3 acute kidney injury (AKI) and severe acidosis (pH≤7.2), NaHCO3 reduced the risk of mortality at day 28 by 18% and death before hospital discharge by 26%. Jaber et al also found that NaHCO3 therapy in patients with stage 2 or 3 AKI and severe acidosis significantly reduced the risk of day 7 organ failure by approximately 16%.6 This trial also demonstrated beneficial effects of NaHCO3 on outcomes related to the utilization of renal replacement therapy in both the overall population and subgroup of patients with AKI; however, a complete discussion of these outcomes is beyond the scope of this review.

Table 1. Mortality outcomes with sodium bicarbonate infusion in patients with metabolic acidosis6,7

Citation

Design & Population

Intervention

Outcomes

Jaber et al6 (2018)

BICAR-ICU

Multicenter (France), OL, RCT

N=389 patients with severe acidemia (pH ≤7.20 and serum NaHCO3 <20 mmol/L) and SOFA score ≥4 or arterial lactate of ≥2 mmol/L

NaHCO3 4.2% (n=195)

Control (n=194)

Overall population (n=389)

  • Composite of death from any cause by day 28 and the presence of ≥ 1 organ failure at day 7 (NaHCO3 vs control): 66% and 71%, respectively (absolute difference, -5.5%; 95% CI, -15.2 to 4.2; p=0.24)
  • Death by day 28 (NaHCO3 vs control): 45% and 54%, respectively; p=0.07

Patients with AKI stage* 2 or 3 (n=182)

  • Composite of death from any cause by day 28 and the presence of ≥ 1 organ failure at day 7 (NaHCO3 vs control): 70% and 82%, respectively (absolute difference, -12.3%; 95% CI, -26 to -0.1; p=0.0462)
  • Death by day 28 (NaHCO3 vs control): 46% and 63%, respectively (absolute difference -17.7; 95% CI, -33 to -2.3; p=0.0166)

Zhang et al7 (2018)

Retrospective cohort study using the Medical Information Mart for Intensive Care databases; propensity matching was utilized

N=1718 patients with sepsis and metabolic acidosis (pH<7.3 and serum NaHCO3 <20 mmol/L) and the absence of respiratory acidosis

NaHCO3 (n=500)

Control (n=1218)

Overall population

  • Death before discharge was similar between groups (HR, 1.04; 95% CI, 0.86 to 1.26; p=0.67)

Patients with AKI stage* 2 or 3 and pH <7.2 (n=251)

  • Death before discharge was lower with NaHCO3 (HR, 0.74; 95% CI, 0.51 to 0.86; p=0.021)

Abbreviations: AKI=acute kidney injury; CI=confidence interval; HR=hazard ratio; NaHCO3 =sodium bicarbonate; OL=open label; RCT=randomized-controlled trial; SOFA= sequential organ failure assessment.

*AKI stages: stage 1 is serum creatinine increase ≥0.3 mg/dL, increase to 1.5 to 2 times from baseline, or urine output <0.5 mL/kg per hour for 6 hours; stage 2 is serum creatinine increase >2 to 3 times from baseline or urine output <0.5 mL/kg per hour for 12 hours; stage 3 is serum creatinine increase >3 times from baseline or serum creatinine ≥4 mg/dL with an acute increase of at least 0.5 mg/dL the need for renal replacement-therapy, or urine output <0.3 mL/kg per hour for 12 hour. AKIN zero means no kidney injury.

Discussion:

Infusions of NaHCO3 have been widely used in critically ill patients with metabolic acidosis, however, evidence supporting their usefulness in improving clinical outcomes are still evolving.2,3,6,7 According to the most recent update of the Surviving Sepsis Campaign guideline, there is a lack of published data describing the impact of NaHCO3 on clinical outcomes.3 Furthermore, earlier clinical trials demonstrated that the increase in arterial pH as a result of NaHCO3 therapy does not translate to increases in hemodynamic variables, including cardiac output and MAP.4,5

Recently, data from an open-label randomized controlled trial and retrospective cohort study have a demonstrated a mortality benefit with NaHCO3 infusion in a subgroup of patients with serum pH < 7.2 or stage 2 or 3 AKI.6,7 Nonetheless, both trials had important limitations. The observational design of Zhang et al prevents the ability to establish causal effects and may have introduced the potential for confounders. Furthermore, the database utilized included patient records dating back more than a decade, therefore, may not reflect other current standards of care for patients with sepsis and metabolic acidosis; adverse effects were also not reported in this trial. On the other hand, Jaber et al failed to standardize the volume of NaHCO3 infused to patients, and the open-label nature of the trial may have introduced performance and detection bias.6 Furthermore, there was heterogeneity in the underlying causes of acidemia, and investigators did not stratify nor analyze patients based on these causes.

In conclusion, newer data has demonstrated a possible mortality benefit and reduction in organ failure with NaHCO3 infusions in the setting of severe metabolic acidosis in a subgroup of patients with AKI. However, more clinical trials confirming these trends are likely needed before widespread changes in practice can occur.

References:

  1. DuBose TD. Acidosis and Alkalosis. In: Jameson J, Fauci AS, Kasper D, Hauser SL, Longo DL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill; 2018. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192013363. Accessed November 21, 2018.
  2. Adeva-Andany MM, Fernandez-Fernandez C, Mourino-Bayolo D, Castro-Quintela E, Dominguez-Montero A. Sodium bicarbonate therapy in patients with metabolic acidosis. The Scientific World Journal.2014;(627673):1-13.
  3. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552.
  4. Cooper DJ, Walley KR, Wiggs BR, et al: Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med 1990;112:492–498
  5. Mathieu D, Neviere R, Billard V, et al: Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit Care Med 1991;19:1352–1356
  6. Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018;392(10141):31-40.
  7. Zhang Z, Zhu C, Mo L, Hong Y. Effectiveness of sodium bicarbonate infusion on mortality in septic patients with metabolic acidosis. Intensive Care Med. 2018;44(11):1888-1895.

Prepared by:

Katherine Sarna, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

December 2018

The information presented is current as of November 20, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What data support use of topical tranexamic acid for epistaxis in adults?

Epistaxis is a frequently encountered condition in the emergency department, with approximately 60% of Americans experiencing nosebleeds in their lifetime.1 Epistaxis is divided based on the bleed location: anterior (approximately 90% of cases), or posterior (approximately 10% of cases) which is more difficult to treat.2 Generally, epistaxis is self-limited but may be difficult to manage in some cases.1 Treatment of epistaxis may include application of pressure, topical anesthetic and vasoconstrictor agents, cauterization (ie, silver nitrate), and nasal packing.3 However, nasal packing has disadvantages, including discomfort, prophylactic antibiotic administration, and the need for an additional visit for removal.4

Recently, topical tranexamic acid has been a treatment of interest for epistaxis. Tranexamic acid, a derivative of lysine, is an antifibrinolytic, hemostatic drug commercially available in the United States as an injectable solution or oral tablet.4-6 Although not commercially available as a topical formulation, tranexamic acid has been used topically for off-label indications, such as to reduce risk of bleeding in surgical patients.7 The purpose of this review is to summarize literature on topical tranexamic acid for epistaxis.

The Table summarizes the available studies evaluating topical tranexamic acid for treatment of epistaxis in adults.

Table. Studies evaluating topical TXA for treatment of epistaxis in adults.8-11

Study citation and design

Subjects

Interventions and administration of TXA

Results

RCTs

Zahed 20188

PG, RCT, at 2 EDs in Iran

Treating providers and patients were unblinded; analysts were blinded

N=124 patients taking antiplatelets (aspirin and/or clopidogrel) with anterior epistaxis with bleeding after 20 minutes of compression of both nostrils

Patients with posterior epistaxis or inherited bleeding disorders were excluded

Age: TXA 58.5 years vs  anterior nasal packing 60.7 years

At baseline, prior epistaxis history was higher in TXA group

Topical TXA-soaked pledgets (described below) (n=62)

Anterior nasal packing (described below) (n=62)

TXA: 15-cm piece of cotton pledget was soaked in injectable TXA 500 mg in 5 mL and inserted into nostril. Removal occurred after physician determined bleeding cessation.

Anterior nasal packing: Cotton pledget soaked in 1:100,000 epinephrine and 2% lidocaine and inserted into the nostril for 10 minutes. Then, several cotton pledgets covered with tetracycline ointment left for 3 days.

Primary (TXA vs anterior nasal packing):

  • Proportion of patients with bleeding stopped within 10 minutes: 73% vs 29% (difference, 44%; 95% CI, 26% to 57%; p<0.001)

Secondary (TXA vs anterior nasal packing):

  • Median time to bleeding cessation: 10 minutes vs 15 minutes (p<0.001)
  • Rebleeding at 24 hours: 5% vs 10% (p=NS)
  • Rebleeding at 7 days: 5% vs 21% (p=0.007)
  • ED discharge ≤ 2 hours: 97% vs 13% (p<0.001)
  • Median patient satisfaction score (1 to 10 scale): 9 vs 4 (p<0.001)
  • Complications (nausea, vomiting, or treatment intolerance): 10% vs 5% (p=NS)
  • No serious AEs reported

Zahed 20139

SC, PG, RCT in Iran

Treating providers and patients were unblinded; analysts were blinded

N=216 patients with idiopathic anterior epistaxis

Patients with posterior epistaxis or inherited bleeding disorders were excluded

Age: TXA 50.4 years vs anterior nasal packing 54 years

At baseline, prior epistaxis history was higher in TXA group

Topical TXA-soaked pledgets (described below) (n=107)

Anterior nasal packing (described below) (n=109)

TXA: 15-cm piece of cotton pledget was soaked in injectable TXA 500 mg in 5 mL and inserted into nostril. Removal occurred after physician determined bleeding cessation.

Anterior nasal packing: Cotton pledget soaked in 1:100,000 epinephrine and 2% lidocaine and inserted into the nostril for 10 minutes. Then, several cotton pledgets covered with tetracycline ointment left for 3 days.

Outcomes (TXA vs anterior nasal packing):

  • Proportion of patients with epistaxis stopped within 10 minutes: 71% vs 31.2% (OR, 2.28; 95% CI, 1.68 to 3.09; p<0.001)
  • Rebleeding within 24 hours: 4.7% vs 12.8% (p=0.034)
  • Rebleeding within 7 days: 2.8% vs 11% (p=0.018)
  • ED discharge ≤ 2 hours: 95.3% vs 6.4% (p<0.001)
  • Patient satisfaction (1 to 10 scale): 8.5 vs 4.4 (p<0.001)
  • Complications (nausea/vomiting and intolerance): 4.7% vs 11% (p=NS)
  • No serious AEs were reported

Tibbelin 199510

DB, MC, PG, RCT in Sweden

N=68 adult patients with ongoing epistaxis (excluded known impaired hemostasis)

Patients were followed for 10 days

Mean age: TXA 50 years vs placebo 65 years

Bleeding location (TXA vs placebo): Kiesselbach’s area (57% vs 55%), Posterior area (30% vs 42%), Superior area (13% vs 3%)

At baseline, moderate and severe bleeding intensity higher in TXA vs placebo (p<0.01)

TXA gel (15 mL) applied locally to the nasal cavity (n=30)

Placebo (glycine) gel (n=38)

TXA 15 mL gel contained 10% TXA in plastic syringe with methargen and propagin for preservatives and carboxypolymethylene for thickening.

The gel was administered into the entire nostril cavity and kept in for 30 min.

Outcomes (TXA vs placebo):

  • Frequency of bleeding arrested within 30 min: 60% vs 76% (p=NS)
  • Frequency of rebleeding within 10 days: 44% vs 66% (p=NS)
  • Patients’ acceptance of treatment: 3 patients per group reported a “bad taste”
  • No serious AEs reported

Retrospective analysis

Birmingham 201811

SC, retrospective chart review in USA

N=122 patients who presented to the ED with a primary diagnosis of epistaxis

Excluded patients who achieved hemostasis solely with first-line agents (oxymetazoline, lidocaine, or epinephrine)

78.3% of patients had anterior bleeds

Median age: TXA 63 years vs standard of care 62 years

At baseline, there were more male patients and LVADs in TXA group vs standard of care

Topical TXA + standard of care (described below) (n=30)

Standard of care (n=92)

TXA: 500 mg injectable TXA solution soaked onto cotton pledget or nasal tampons (n=29) or 100 mg aerosolized (n=1)

Initial treatment:

TXA: First-line agents (53.3%) and TXA ± first-line agents (46.7%)

Standard of care: First-line agents (79.3%), nasal packing (14.1%) and silver nitrate cauterization (6.5%)

Primary (TXA vs standard of care):

  • Median ED LOS: 272 vs 232 min (p=NS)

Secondary (TXA vs standard of care):

  • Incidence of hospital admission: 20% vs 26.1% (p=NS)
  • Otolaryngologist consultation: 30% vs 65.2% (p=0.002)
  • Nasal packing: 46.7% vs 76.1% (p=0.003)
  • Prophylactic antibiotic use: 13.3% vs 17.4% (p=NS)
  • ED visit for rebleeding within 7 days: 23.3% vs 19.6% (p=NS)
  • No thrombotic events were recorded at 10 days

Abbreviations: AE=adverse event; CI=confidence interval; DB=double blind; ED=emergency department; LOS=length of stay; LVAD=left ventricular assist device; MC=multi-center; NS=not significant; OR=odds ratio; PG=parallel group; RCT=randomized controlled trial; SC=single center; TXA=tranexamic acid.

Literature Summary

Clinical studies evaluating the use of topical tranexamic acid for epistaxis include 3 randomized controlled trials and 1 retrospective chart review. The studies have different study populations, method of topical tranexamic acid administration, and comparator groups making overall conclusions difficult. Two randomized controlled trials by Zahed and colleagues compared topical tranexamic acid soaked pledgets to anterior nasal packing in patients with anterior epistaxis.8,9 In the 2018 study, patients were also taking antiplatelet agents.8 Topical tranexamic acid resulted in improved rate of bleeding cessation within 10 minutes, lower rate of rebleeding, and shorter emergency department length of stay in both studies.8,9 No serious adverse events were reported. In these studies, only data analysts were blinded and other treatments were not discussed. A 1995 randomized controlled trial by Tibbelin et al compared a topical tranexamic acid gel to placebo (glycerin) gel; however, there were no differences in efficacy between the groups.10 No serious adverse events were reported. In this study, more patients had posterior bleeds (30% in tranexamic acid group and 42% in placebo group) compared to the studies by Zahed et al, which only included patients with anterior bleeds.8-10 Additionally, more patients in the tranexamic acid group had moderate to severe bleeding at baseline.10 Finally, a 2018 retrospective review by Birmingham and colleagues compared topical tranexamic acid to the standard of care in patients with mostly anterior epistaxis (78.3%).11 This study included patients with bleeding disorders. There was no difference between groups in emergency department length of stay, but otolaryngologist consultation and nasal packing were lower with tranexamic acid. Data regarding safety in epistaxis is limited, although a 2018 meta-analysis of topical tranexamic acid used for a variety of indications, mostly in surgery, did not find an increased risk of venous thromboembolic complications, stroke, or myocardial infarction compared to placebo.7

Administration Techniques in Studies

There have been various techniques used to apply topical tranexamic acid. In clinical studies, the most common technique, as used in 2 randomized controlled trials by Zahed and colleagues, was soaking a 15 cm cotton pledget in injectable tranexamic acid (500 mg in 5 mL) and inserting it into nostril until bleeding cessation.8,9 Similarly, in the 2018 retrospective chart review by Birmingham and colleagues performed in the United States, 29 of 30 patients received a cotton pledget or nasal tampon soaked in 500 mg injectable tranexamic acid, while 1 of the patients received 100 mg tranexamic acid aerosolized.11 The study by Tibbelin et al used application of 15 mL of a 10% tranexamic acid gel, but there were no statistical differences in efficacy between the tranexamic gel and placebo gel.10

Conclusion

Topical tranexamic acid is a promising treatment for epistaxis; however, due to varying study populations and comparator groups in clinical trials, the exact role in treatment is not well-defined. If used for epistaxis, studies that found a benefit with topical tranexamic acid administered it by soaking a cotton pledget in injectable tranexamic acid 500 mg then inserting it into the affected nostril.

References

1.         Lai S, Waxman M. Epistaxis management. In: Reichman EF, eds. Reichman's Emergency Medicine Procedures. 3rd ed.  New York, NY: McGraw-Hill; 2019. http://accessemergencymedicine.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=2498&sectionid=201302233. Accessed November 16, 2018.

2.         Senecal EL. Epistaxis. In: Sherman SC, Weber JM, Schindlbeck MA, Rahul G. P, eds. Clinical Emergency Medicine. 1st ed. New York, NY: McGraw-Hill; 2014. http://accessemergencymedicine.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=991&sectionid=55139195. Accessed November 16, 2018.

3.         Kasperek ZA, Pollock GF. Epistaxis: an overview. Emerg Med Clin North Am. 2013;31(2):443-454.

4.         Logan J, Pantle H. Role of topical tranexamic acid in the management of idiopathic anterior epistaxis in adult patients in the emergency department. Am J Health Syst Pharm. 2016;73(21):1755-1759.

5.         Clinical Pharmacology powered by ClinicalKey. 2018. http://clinicalpharmacology.com/. Accessed November 16, 2018.

6.         Anonymous. Orange book: Approved drug products with therapeutic equivalence evaluations. 2018. https://www.accessdata.fda.gov/scripts/cder/ob/. Accessed November 16, 2018.

7.         Montroy J, Hutton B, Moodley P, et al. The efficacy and safety of topical tranexamic acid: A systematic review and meta-analysis [published online ahead of print February 19, 2018]. Transfus Med Rev. doi: 10.1016/j.tmrv.2018.02.003.

8.         Zahed R, Mousavi Jazayeri MH, Naderi A, Naderpour Z, Saeedi M. Topical tanexamic acid compared with anterior nasal packing for treatment of epistaxis in patients taking antiplatelet drugs: randomized controlled trial. Acad Emerg Med. 2018;25(3):261-266.

9.         Zahed R, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013;31(9):1389-1392.

10.       Tibbelin A, Aust R, Bende M, et al. Effect of local tranexamic acid gel in the treatment of epistaxis. ORL J Otorhinolaryngol Relat Spec. 1995;57(4):207-209.

11.       Birmingham AR, Mah ND, Ran R, Hansen M. Topical tranexamic acid for the treatment of acute epistaxis in the emergency department. Am J Emerg Med. 2018;36(7):1242-1245.

Prepared by:

Patricia Hartke, PharmD

Clinical Assistant Professor

College of Pharmacy

University of Illinois at Chicago

December 2018

The information presented is current as of October 1, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making

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What is the evidence for online vancomycin dose calculators?

Background

In 2009, the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) released a consensus review on therapeutic monitoring of vancomycin in adult patients.1 The recommendations involve detailed information on trough monitoring and potential dosing recommendations for vancomycin. Daily doses should be 15 to 20 mg/kg based on actual body weight (ABW) and given every 8 to 12 hours in patients with normal renal function. In seriously ill patients, a loading dose of 25 to 30 mg/kg (based on ABW) helps achieve a target serum concentration more rapidly. For complicated infections, vancomycin trough concentration should be above 15 to 20 mg/L, while concentrations above 10 mg/L are sufficient for other infections. A 2012 cross-sectional survey showed a lack of consistency among US hospitals in adhering to guidelines especially in terms of timing of trough concentrations, use of loading doses, and use of ABW.2 A retrospective study of the implementation of a vancomycin order set as part of the computerized prescriber order entry (CPOE) improved adherence to vancomycin dosing based on the guideline from 34.9% to 51% (p<0.001).3 Therefore, the utilization of vancomycin calculators has the potential to improve adherence to the guideline and to determine appropriate vancomycin dosing in special populations such as patients who are obese or have renal impairment.  Numerous methods are available for calculating vancomycin dosing: nomograms, computer programs, and website calculators.4 The goal of this article is to review available evidence on the use of vancomycin dosing calculators, with a focus on freely available calculators.

Impact of vancomycin calculators

The published literature regarding vancomycin calculators is limited, and the available studies focus mainly on positive outcomes after implementation of a vancomycin or antibiotic calculator. A retrospective study by Wang and colleagues revealed a reduction in incorrect antibiotic dosing by 80% after implementation of a dosing calculator for 13 renally-cleared antibiotics in the CPOE.5 The use of calculators also lowered the deterioration of renal function from 12.4% to 9.5%. This study did not include a calculator for vancomycin. A pre- and post-intervention study by Hamad and colleagues found that the implementation of intranet calculators in a 950-bed teaching hospital resulted in a reduction of incorrect vancomycin loading doses from 58.1% to 32.4% (p<0.001) and a reduction of incorrect first maintenance doses from 55.5% to 33.1% (p<0.001).6 The vancomycin dosing calculator was in Excel format available on the hospital intranet. A study evaluating the implementation of a model-based vancomycin calculator revealed an increase in the percentage of neonates achieving vancomycin target concentration of 15 to 25 mg/L with a first vancomycin level from 41% to 72%.7 The vancomycin calculator was developed in Excel based on the results from a population pharmacokinetic model.

Methods for vancomycin dose calculations

Numerous vancomycin dose calculators are available, and many of them use different formulas.4 The majority of calculations primarily depend on 2 variables: volume of distribution (V) and elimination rate (K). Many vancomycin formulas and calculators utilize Gary Matzke’s equations, which is K = 0.00083 x CrCl + 0.0044, where CrCl is creatinine clearance calculated by using ideal body weight (IBW).4,8

Several vancomycin dosing calculators are freely available online:

GlobalRph.com and ClinCalc.com use a similar formula for vancomycin dose calculation, which is based on Gary Matzke’s equation, see Table 1.4 Both calculators base CrCl calculation on IBW in the Cockcroft-Gault equation for most patients and ABW for underweight patients.9,10 They use adjusted body weight (AjBW) in the Cockcroft-Gault equation for obese patients. SurgicalCriticalCare.net calculator is based on a nomogram mainly helpful for estimating initial doses and dosing intervals.4,11 This calculator does not incorporate peak and trough levels and does not individualize doses. Vancomycin-calculator.com was created by pharmacists from the Department of Veterans Affairs in Texas and uses the Bauer method, see Table 1.4,12

The comparative literature of various vancomycin calculators is lacking. In a review article, Farewell made calculation comparisons for vancomycin dosing among Globalrph.com, ClinCalc.com, SurgicalCriticalCare.net, and Vancomycin-Calculator.com calculators.4 SurgicalCriticalCare.net and Vancomycin-Calculator.com yielded higher doses for normal body weight and the underweight patients, respectively, compared to the rest of calculators. For obese patients, initial and adjustment doses for vancomycin were different among all of the calculators. This may be due to different formulas used in each calculator, see Table 1. Statistical analyses were not performed in the review article.

Table 1. Formulas for vancomycin dosing.4,9-12

Calculator

Formulas

Vancomycin-Calculator.com

K (h-1): K = Cl/V, where Cl = [(0.695 x CrCl/ABW) + 0.05] x (ABW x 0.06)

Dosing interval (h): T = ln(Cmax/Cmin)/K

Maintenance dose (mg): Dose = (Peak x V)(1 – e-KxT)

GlobalRph.com

K (h-1): K = 0.00083 x CrCl + 0.0044

• Dosing interval (h): T = [ln(Cmax/Cmin)/K] + ti

• Maintenance dose (mg): Dose = [K x V x ti x desired peak x (1 – e-KxT)]/(1 – e-Kxti)

ClinCalc.com

K (h-1): K = 0.00083 x CrCl + 0.0044

• Dosing interval (h): T = [ln(Cmax/Cmin)/K] + ti

• Maintenance dose (mg): Dose = [K x V x ti x desired peak x (1 – e-KxT)]/(1 – e-Kxti)

SurgicalCriticalCare.net

Nomogram

Abbreviations: ABW = actual body weight; Cl =vancomycin clearance; Cmin = minimum serum concentration (trough); Cmax = maximum serum concentration (peak); CrCl = creatinine clearance; K = elimination rate; T = dosing interval; ti = infusion time; V = volume of distribution.

Conclusion

The published literature regarding vancomycin calculators is limited.  The available studies show that implementation of an antibiotic or vancomycin calculator in a hospital can improve the rate of correct doses, decrease renal function deterioration, and achieve target serum concentrations faster. Unfortunately, the comparative literature of various vancomycin calculators is lacking. Several vancomycin dosing calculators are freely available online: GlobalRPh.com, ClinCalc.com, SurgicalCriticalCare.net, and Vancomycin-calculator.com. These calculators vary in calculated doses for vancomycin, especially for obese patients. Therefore, pharmacists and providers must be aware of differences among these calculators and use clinical judgment when deciding on a vancomycin dose especially in special populations such as patients who are obese or have renal impairment. Future comparative studies among freely available calculators would aid clinicians in choosing the best resource for calculations.

References:

1.         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.

2.         Davis SL, Scheetz MH, Bosso JA, Goff DA, Rybak MJ. Adherence to the 2009 consensus guidelines for vancomycin dosing and monitoring practices: a cross-sectional survey of U.S. hospitals. Pharmacotherapy. 2013;33(12):1256-1263.

3.         Frankel KC, Rosini JM, Levine BJ, Papas MA, Jasani NB. Computerized provider order entry improves compliance of vancomycin dosing guidelines in the emergency department. Am J Emerg Med. 2013;31(12):1715-1716.

4.         Fewel NP. Comparison of open-access vancomycin dosing websites. J Clin Pharm Ther. 2017;42(2):128-131.

5.         Wang HY, Lu CL, Wu MP, Huang MH, Huang YB. Effectiveness of an integrated CPOE decision-supporting system with clinical pharmacist monitoring practice in preventing antibiotic dosing errors. Int J Clin Pharmacol Ther. 2012;50(6):375-382.

6.         Hamad A, Cavell G, Hinton J, Wade P, Whittlesea C. A pre-postintervention study to evaluate the impact of dose calculators on the accuracy of gentamicin and vancomycin initial doses. BMJ Open. 2015;5(6):e006610.

7.         Leroux S, Jacqz-Aigrain E, Biran V, et al. Clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. Antimicrob Agents Chemother. 2016;60(4):2039-2042.

8.         Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother. 1984;25(4):433-437.

9.         Aminoglycosides and vancomycin dosing (original calculator). GlobalRph website. https://globalrph.com/medcalcs/aminoglycosides-and-vancomycin-original-calculator/. Accessed November 7, 2018.

10.       Vancomycin calculator: advanced vancomycin pharmacokinetics tool. ClinCalc.com website. https://clincalc.com/Vancomycin/default.aspx. Updated November 3, 2018. Accessed November 7, 2018.

11.       Vancomycin dosing calculator. SurgicalCriticalCare.net website. http://www.surgicalcriticalcare.net/Resources/vancomycin.php. Accessed November 7, 2018.

12.       Vancomycin calculator. Vancomycin-calculator.com website. https://www.vancomycin-calculator.com/. Updated October 26, 2018. Accessed November 7, 2018.

Prepared by:

Janna Afanasjeva, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

December 2018

The information presented is current as of November 7, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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