NOTES Diuretic stewardship program
NOTES
Implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit to reduce medication expenditures Christopher A. Thomas, Jennifer L. Morris, Elizabeth A. Sinclair, Richard H. Speicher, Sheikh S. Ahmed, and Alexandre T. Rotta
C
apillary leak, fluid overload, and edema are common consequences of cardiopulmonary bypass in infants and children after cardiac surgery.1,2 High-dose diuretics are often used to reverse these effects in an attempt to reduce the duration of mechanical ventilation and the length of stay after cardiac surgeries involving cardiopulmonary bypass.3,4 Diuretics commonly used in pediatric patients for this indication are inordinately expensive without robust data to support their use over inexpensive options. In addition, robust data regarding the use of combination diuretic therapy in adult and pediatric patients in the cardiovascular intensive care unit (ICU) are scarce.5,6 Due to the use of expensive medications, the pharmacy drug budget
Purpose. The implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit (ICU) is described. Methods. This retrospective study compared the use of i.v. chlorothiazide and i.v. ethacrynic acid in pediatric cardiovascular surgery patients before and after implementation of a diuretic stewardship program. All pediatric patients admitted to the pediatric cardiovascular service were included. The cardiovascular surgery service was educated on formal indications for specific diuretic agents, and the diuretic stewardship program was implemented on January 1, 2013. Under the stewardship program, i.v. ethacrynic acid was indicated in patients with a sulfonamide allergy, and i.v. chlorothiazide was considered appropriate in patients receiving maximized i.v. loop diuretic doses. A detailed review of the pharmacy database and medical records was performed for each patient to
Christopher A. Thomas, Pharm.D., is Clinical Pharmacy Specialist— Pediatric Cardiovascular Intensive Care Unit (ICU), Department of Pharmacy, Riley Hospital for Children at Indiana University Health (IUH), Indianapolis; at the time of writing he was Clinical Pharmacy Specialist—Pediatric Cardiovascular ICU, Department of Pharmacy Services, Phoenix Children’s Hospital, Phoenix, AZ. Jennifer L. Morris, Pharm.D., is Clinical Pharmacy Specialist—Pediatric ICU, Department of Pharmacy Services, Texas Children’s Hospital, Houston; at the time of writing she was Clinical Pharmacy Specialist—Pediatric ICU, Department of Pharmacy Services, Riley Hospital for Children at IUH. Elizabeth A. Sinclair, Pharm.D., is Clinical Pharmacy Specialist—Pediatric ICU, Department of Pharmacy Services, Texas Children’s Hospital, Houston. Richard H. Speicher, M.D., is Medical Director, Pediatric ICU, Division of Pediatric Critical Care, Rainbow Babies and Children’s Hospital, Cleveland, OH, and Assistant Professor, Department of Pediatrics,
determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. Results. After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of $91,398 in expenditures on these diuretics over the six-month study period and an estimated annual saving of over $182,000. The median number of days using a ventilator and the length of ICU stay did not differ significantly during the study period. Conclusion. Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as ventilator days and length of stay in a pediatric cardiovascular ICU. Am J Health-Syst Pharm. 2015; 72:1047-51
School of Medicine, Case Western Reserve University, Cleveland. Sheikh S. Ahmed, M.D., is Assistant Professor of Clinical Pediatrics, Section of Pediatric Pulmonology, Critical Care and Allergy, Riley Hospital for Children at IUH. Alexandre T. Rotta, M.D., is Chief, Division of Pediatric Critical Care, Rainbow Babies and Children’s Hospital, and Professor, Department of Pediatrics, School of Medicine, Case Western Reserve University. Address correspondence to Dr. Thomas ([email protected]). Presented in part at the Society of Critical Care Medicine’s 43rd Critical Care Congress, San Francisco, CA, January 2014. The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0602-1047. DOI 10.2146/ajhp140532
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1047
NOTES Diuretic stewardship program
has a notable effect on institutional finances, as drug acquisition costs continue to be a rapidly proliferating healthcare expenditure.7 The Centers for Medicare and Medicaid Services estimated that U.S. prescription drug expenditures will increase 6.5% per year from 2015 through 2022.8 Thus, it is vitally important for health systems to control costs by implementing measures that legitimize and prioritize pharmacoeconomically sound prescribing practices. The development of medication-use management initiatives (e.g., antibiotic stewardship) and the provision of clinical pharmacy services (e.g., pharmacist-directed anticoagulation management) are just two examples that have been proven to help curtail hospital drug expenditures.7 Diuretic stewardship, however, has not been previously described in the clinical literature. The average wholesale prices of the most commonly used diuretics in pediatric patients differ appreciably. Table 1 lists specific wholesale prices for commonly used diuretics as reported through our wholesaler at initiation of the study. Scant data have been reported to support the use of high-cost agents over less-expensive options for pediatric patients in the cardiovascular ICU. Due to the anecdotally high use of i.v. chlorothiazide and i.v. ethacrynic acid in the study institution, the pharmacy
department and the pediatric cardiovascular surgery team developed and implemented a diuretic stewardship program in an attempt to curtail the prescribing patterns for expensive diuretics while avoiding adverse effects on patient care. The evaluation and validation of this program could lead to more cost-effective diuretic therapy by promoting the maximized use of inexpensive loop diuretics and oral thiazide diuretics before i.v. chlorothiazide in pediatric patients undergoing cardiothoracic surgery. The primary objective of this study was to evaluate the effectiveness of a diuretic stewardship program in a pediatric cardiovascular ICU in reducing pharmacy drug expenditures related to the use of i.v. chlorothiazide and i.v. ethacrynic acid. The secondary objectives were to assess the impact of the diuretic stewardship program on surrogate markers of in-hospital morbidity and to evaluate the appropriate use of i.v. chlorothiazide and i.v. etha crynic acid before and after program inception. Methods A diuretic stewardship program was implemented on the pediatric cardiovascular surgery service at Riley Hospital for Children in Indianapolis, Indiana, on January 1, 2013. Information regarding the appropriate indications, dosing, and
Table 1.
Wholesale Prices of Diuretics Drug
Strength
Price (U.S. Dollars)a
Bumetanide 2.5 mg/10 mL (i.v.), 0.5 mg (oral) $0.18/vial, $0.34/tablet Ethacrynic acid 50 mg (i.v.) $905.00/vial Furosemide 20 mg/2 mL (i.v.), $0.10/mL, 10 mg/mL (oral solution) $1.05/vial Chlorothiazide 500 mg (i.v.), 500 mg (oral) $348.00/vial, $1.24/tablet Hydrochlorothiazide 12.5 mg (oral) $0.20/capsule Metolazone 2.5 mg (oral) $1.48/tablet As of August 2013.
a
1048
Am J Health-Syst Pharm—Vol 72 Jun 15, 2015
costs of various diuretic agents was distributed via e-mail to all pediatric cardiac intensivists (n = 8), cardiovascular surgeons (n = 3), cardiologists (n = 15), and nurse practitioners (n = 6) who cared for patients on the cardiovascular surgery service. After this information was provided, pharmacy interventions were performed by the pediatric critical care clinical pharmacy specialists for i.v. chlorothiazide and i.v. ethacrynic acid doses that did not meet the criteria for appropriate use. Although interventions were not made on every dose ordered, these interventions consisted of real-time guidance and feedback during daily clinical rounds, live or telephonic communication with prescribers, one quarterly update on the progress of the program, and continued education on the use and indications of the various diuretic agents. No changes were made to any order sets or clinical decision support within the computerized prescriberorder-entry system. Appropriate use of i.v. chlorothiazide was defined as any patient receiving one of the following: i.v. furosemide ≥1 mg/kg every six hours, continuous i.v. furosemide infusion ≥0.2 mg/kg/hr, any strength of i.v. bumetanide every six hours, or any strength of a continuous i.v. bumetanide infusion. A weight-based dose for bumetanide was not specified due to lack of consensus at our institution regarding equivalent dose ranges when compared with furosemide. I.V. ethacrynic acid was considered appropriate only in patients with a documented sulfonamide allergy. This study was reviewed and approved by the Indiana University institutional review board. Six months after the diuretic stewardship program was implemented, the pharmacy database and electronic medical records were retrospectively queried to identify patients for inclusion from January 1 through June 30 in both 2012 and 2013. All patients admitted to the
NOTES Diuretic stewardship program
pediatric ICU and cared for by the cardiovascular ICU service after cardiac surgery during the study period were included. Patients admitted to the pediatric ICU and cared for by the pediatric critical care service were excluded. A detailed review of the pharmacy database and medical records was performed for each patient to determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. Data were analyzed with the Mann– Whitney U test. The a priori level of significance was 0.05. Results The number of patients undergoing cardiovascular surgery was relatively consistent during the first two quarters of 2012 and 2013 (149 and 163, respectively). After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of $91,398 in expenditures on these diuretics over the six-month study period and an estimated annual savings of over $182,000 (Table 2). Although appropriate prescribing patterns of i.v. chlorothiazide improved by 4.5%, the number of patients and the duration of use were notably attenuated, leading to an 85% reduction ($58,327) in money spent on inappropriate doses of i.v. chlorothiazide and ethacrynic acid combined. In addition, the median number of days using a ventilator (one day in 2012 and 2013) and the length of ICU stay (four days in 2012 versus three days in 2013) did not differ significantly during the study period. Discussion Combination diuretic therapy with thiazide diuretics is used to augment loop diuretic therapy and to overcome diuretic resistance in
cardiac surgery patients.5,9 Despite the prevalence of this practice, data linking this practice to improved outcomes are limited. Jentzer and colleagues5 reviewed data on the use of combination diuretic therapy in adult heart failure patients. Their review covered the entire adult heart failure literature base but involved only about 300 patients in 50 reports. In 2013, Ng and colleagues6 conducted a retrospective study, which remains the single most robust study to date, reviewing single and combination diuretic therapy in 242 adult patients with acute heart failure. This report compared patients who initially received intermittent furosemide therapy that was later changed to continuous-infusion furosemide, a combination of furosemide and metolazone, or continuous-infusion bumetanide. The authors found all three of the escalated regimens resulted in higher urine output compared to intermittent furosemide therapy. Additionally, they concluded that patients who received furosemide plus metolazone and those who received continuous-infusion bumetanide had a better response
compared to continuous-infusion furosemide. Although the body of literature regarding combination diuretic therapy among adult patients remains sparse, combination diuretic therapy reports for pediatric patients are even rarer and mostly limited to small retrospective studies and case reports in noncardiacsurgery patients.5,6,9-12 Although this investigation primarily focused on the pharmacoeconomic impact of diuretic stewardship, to our knowledge it is the first to link outcomes and combination diuretic therapy in pediatric patients. Smith and colleagues13 recently reported dramatic increases in healthcare resources used for 13,156 neonatal congenital heart patients in 2005–11. They reported an increase in total pharmacy charges of 16% per patient case (from $39,441 to $45,743) and found i.v. chlorothiazide to be one of the top two drugs accounting for the increase. I.V. chlorothiazide use increased from 26% of patients in 2005 to 37% of patients in 2011, resulting in a 755% increase in charges per patient case (from $886 in 2005 to $7,582 in 2011).
Table 2.
Characteristics of I.V. Chlorothiazide and Ethacrynic Acid Use Among Patients Undergoing Cardiovascular Surgery in 2012 and 2013 Variable
2012 (n = 149)
2013 (n = 163)
I.V. chlorothiazide Patients, no. (%) 53 (35.5) 30 (18.4) Doses, no. 716 185 Doses/patient 4.81 1.13 Appropriate doses, no. (%) 471 (65.8) 130 (70.3) Cost, $ 75,111 23,260 Cost of inappropriate doses, $ 25,688 6,908 I.V. ethacrynic acid Patients, no. (%) 29 3 Doses, no. 51 4 Doses/patient 0.34 0.02 Appropriate doses, no. (%) 0 0 Cost of inappropriate doses, $ 42,913 3,366 Total cost, $ 118,024 26,626 Total cost of inappropriate doses, $ 68,601 10,274
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NOTES Diuretic stewardship program
In addition, few data exist on the use of i.v. ethacrynic acid as a first-line loop diuretic outside of the clinical scenario of potential allergic cross-reactivity in patients with a documented sulfonamide allergy. Although the use of i.v. ethacrynic acid meaningfully decreased during our study period, the rate of appropriate use remained unchanged at 0%. We believe the decreased use of this drug combined with the cost savings of nearly $40,000 in a six-month period highlights the success of this program, despite the continued inappropriate use of ethacrynic acid after the study interventions. We believe that the inappropriate use of ethacrynic acid remained 100% in both study periods due to the low rate (0%) of patients in the study with a documented sulfonamide allergy, combined with the fact that not all doses were accompanied with a formal educational intervention by the clinical pharmacist. More study is needed to evaluate the role of ethacrynic acid as a first-line diuretic before using inexpensive options such as furosemide and bumetanide in patients without a sulfonamide allergy. With the lack of data supporting the use of first-line i.v. ethacrynic acid or the addition of i.v. chlorothiazide before maximizing loop diuretic therapy, it may be clinically and pharmacoeconomically appropriate to limit the use of these agents to certain clinical scenarios. The cost of i.v. chlorothiazide to institutions is approximately 360 times more than that of i.v. furosemide. Compared with hydrochlorothiazide and metolazone, i.v. chlorothiazide is 2500 and 220 times more expensive, respectively.14 Due to these extreme differences in institutional drug acquisition costs, we believe it is reasonable to maximize inexpensive loop diuretic therapy and use oral hydrochlorothiazide or metolazone before using i.v. chlorothiazide. Although we observed only a marginal increase in the percentage 1050
of appropriately prescribed doses of i.v. chlorothiazide after implementation of the stewardship program, the absolute number of inappropriately prescribed doses was greatly reduced due to the dramatic decrease in the overall utilization of i.v. chlorothiazide in the cardiovascular ICU, despite the increased number of surgeries in 2013. The diuretic stewardship program successfully decreased the use of i.v. chlorothiazide and i.v. ethacrynic acid in all patients admitted to the cardiovascular ICU, which was the goal. We believe this was the result of the education provided regarding the extreme cost differential between i.v. chlorothiazide and i.v. ethacrynic acid and other inexpensive i.v. and oral diuretic options. We believe prescribers were much less willing to use i.v. chlorothiazide and i.v. ethacrynic acid than they were before the program’s interventions, resulting in decreased overall utilization of i.v. chlorothiazide by 3.68 doses per patient case and i.v. ethacrynic acid by 0.32 dose per patient case in nearly identical patient populations from 2012 through 2013. The savings realized by the hospital for i.v. chlorothiazide and i.v. ethacrynic acid during the six-month study period exceeded $90,000 while the ICU length of stay and days on mechanical ventilation remained the same between study periods, alleviating concerns that the cost saving realized from this stewardship measure would be negated by increased expenditures elsewhere or decreased quality of care. During a time in which institutions aim to cut expenses, a diuretic stewardship program is an attractive option for hospitals to consider in an effort to cut costs without compromising patient care. An important aspect of the development and implementation of a successful diuretic stewardship program, however, is sustainability. Antimicrobial stewardship programs have reported that sustainability is most
Am J Health-Syst Pharm—Vol 72 Jun 15, 2015
attainable when both passive (e.g., education via e-mail or newsletters) and active (e.g., one-on-one interventions) approaches to stewardship are exercised.15 We believe such strategies were paramount to the success of the program and will be essential to its future sustainability. Our study had some limitations. Although we are confident that all cases and drug utilization patterns were captured during data collection, the retrospective nature of the study limited the ability to make observations with the precision and granularity of a prospective study. We attempted to account for potential variation in patient populations by studying comparable time periods during which the variation in patient population would be minimized; January through June encompasses a large portion of the respiratory viral season, and early summer brings high numbers of surgeries to our institution. Although the number of patients included in this study was relatively small, to our knowledge it represents the only collection of pediatric patients to date for whom a diuretic stewardship program has been used. In addition, this is the largest report of i.v. chlorothiazide use in pediatric cardiovascular surgery patients to date. It is our hope that the results of this study will motivate other centers to adopt similar practices in an effort to provide high-quality healthcare while simultaneously incorporating optimal pharmacoeconomic practices for pediatric cardiovascular surgery patients. Future steps to further optimize this program will include the incorporation of clinical decision support within the computerized prescriber-order-entry system. Conclusion Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as
NOTES Diuretic stewardship program
ventilator days and length of stay in a pediatric cardiovascular ICU. References 1. Kozik DJ, Tweddell JS. Characterizing the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. 2006; 81:S2347-54. 2. Jones TJ, Elliott MJ. Paediatric CPB: bypass in a high risk group. Perfusion. 2006; 21:229-33. 3. Van der Vorst MM, Ruys-Dudok van Heel I, Kist-van Holthe JE et al. Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery. Intensive Care Med. 2001; 27:711-5. 4. Schoemaker RC, van der Vorst MM, van Heel IR et al. Development of an optimal furosemide infusion strategy in infants with modeling and simulation. Clin Pharmacol Ther. 2002; 72:383-90. 5. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010; 56:1527-34. 6. Ng TM, Konopka E, Hyderi AF et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther. 2013; 18:345-53. 7. American Society of Health-System Pharmacists. ASHP guidelines on medication cost management strategies for hospitals and health systems. Am J Health-Syst Pharm. 2008; 65:1368-84. 8. Centers for Medicare and Medicaid Services. National health expenditure projections 2012-2022: forecast summary. www.cms.gov/Research-StatisticsData-and-Systems/Statistics-Trends-andReports/NationalHealthExpendData/ downloads/proj2012.pdf (accessed 2014 Nov 6). 9. Cachero SD, Lofland G, Springate JE, Feld LG. Combination of metolazone and furosemide in the treatment of edema in the first month of life. Child Nephrol Urol. 1990; 10:161-3. 10. Arnold WC. Efficacy of metolazone and furosemide in children with furosemideresistant edema. Pediatrics. 1984; 74:872-5. 11. Garin EH. A comparison of combinations of diuretics in nephrotic edema. Am J Dis Child. 1987; 141:769-71. 12. Segar JL, Robillard JE, Johnson KJ et al. Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia. J Pediatr. 1992; 120:966-73. 13. Smith AH, Gay JC, Patel NR. Trends in resource utilization associated with the inpatient treatment of neonatal congenital heart disease. Congenit Heart Dis. 2014; 9:96-105. 14. Society of Critical Care Medicine. Drug shortage alert: November 15, 2012. www. learnicu.org/Lists/Web%20Contents/ Attachments/9640/DrugShortageAlert, %2011.15.12.pdf 15. Tamma PD, Cosgrove SE. Antimicrobial stewardship. Infect Dis Clin North Am. 2011; 25:245-60.
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NOTES
Implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit to reduce medication expenditures Christopher A. Thomas, Jennifer L. Morris, Elizabeth A. Sinclair, Richard H. Speicher, Sheikh S. Ahmed, and Alexandre T. Rotta
C
apillary leak, fluid overload, and edema are common consequences of cardiopulmonary bypass in infants and children after cardiac surgery.1,2 High-dose diuretics are often used to reverse these effects in an attempt to reduce the duration of mechanical ventilation and the length of stay after cardiac surgeries involving cardiopulmonary bypass.3,4 Diuretics commonly used in pediatric patients for this indication are inordinately expensive without robust data to support their use over inexpensive options. In addition, robust data regarding the use of combination diuretic therapy in adult and pediatric patients in the cardiovascular intensive care unit (ICU) are scarce.5,6 Due to the use of expensive medications, the pharmacy drug budget
Purpose. The implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit (ICU) is described. Methods. This retrospective study compared the use of i.v. chlorothiazide and i.v. ethacrynic acid in pediatric cardiovascular surgery patients before and after implementation of a diuretic stewardship program. All pediatric patients admitted to the pediatric cardiovascular service were included. The cardiovascular surgery service was educated on formal indications for specific diuretic agents, and the diuretic stewardship program was implemented on January 1, 2013. Under the stewardship program, i.v. ethacrynic acid was indicated in patients with a sulfonamide allergy, and i.v. chlorothiazide was considered appropriate in patients receiving maximized i.v. loop diuretic doses. A detailed review of the pharmacy database and medical records was performed for each patient to
Christopher A. Thomas, Pharm.D., is Clinical Pharmacy Specialist— Pediatric Cardiovascular Intensive Care Unit (ICU), Department of Pharmacy, Riley Hospital for Children at Indiana University Health (IUH), Indianapolis; at the time of writing he was Clinical Pharmacy Specialist—Pediatric Cardiovascular ICU, Department of Pharmacy Services, Phoenix Children’s Hospital, Phoenix, AZ. Jennifer L. Morris, Pharm.D., is Clinical Pharmacy Specialist—Pediatric ICU, Department of Pharmacy Services, Texas Children’s Hospital, Houston; at the time of writing she was Clinical Pharmacy Specialist—Pediatric ICU, Department of Pharmacy Services, Riley Hospital for Children at IUH. Elizabeth A. Sinclair, Pharm.D., is Clinical Pharmacy Specialist—Pediatric ICU, Department of Pharmacy Services, Texas Children’s Hospital, Houston. Richard H. Speicher, M.D., is Medical Director, Pediatric ICU, Division of Pediatric Critical Care, Rainbow Babies and Children’s Hospital, Cleveland, OH, and Assistant Professor, Department of Pediatrics,
determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. Results. After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of $91,398 in expenditures on these diuretics over the six-month study period and an estimated annual saving of over $182,000. The median number of days using a ventilator and the length of ICU stay did not differ significantly during the study period. Conclusion. Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as ventilator days and length of stay in a pediatric cardiovascular ICU. Am J Health-Syst Pharm. 2015; 72:1047-51
School of Medicine, Case Western Reserve University, Cleveland. Sheikh S. Ahmed, M.D., is Assistant Professor of Clinical Pediatrics, Section of Pediatric Pulmonology, Critical Care and Allergy, Riley Hospital for Children at IUH. Alexandre T. Rotta, M.D., is Chief, Division of Pediatric Critical Care, Rainbow Babies and Children’s Hospital, and Professor, Department of Pediatrics, School of Medicine, Case Western Reserve University. Address correspondence to Dr. Thomas ([email protected]). Presented in part at the Society of Critical Care Medicine’s 43rd Critical Care Congress, San Francisco, CA, January 2014. The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0602-1047. DOI 10.2146/ajhp140532
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NOTES Diuretic stewardship program
has a notable effect on institutional finances, as drug acquisition costs continue to be a rapidly proliferating healthcare expenditure.7 The Centers for Medicare and Medicaid Services estimated that U.S. prescription drug expenditures will increase 6.5% per year from 2015 through 2022.8 Thus, it is vitally important for health systems to control costs by implementing measures that legitimize and prioritize pharmacoeconomically sound prescribing practices. The development of medication-use management initiatives (e.g., antibiotic stewardship) and the provision of clinical pharmacy services (e.g., pharmacist-directed anticoagulation management) are just two examples that have been proven to help curtail hospital drug expenditures.7 Diuretic stewardship, however, has not been previously described in the clinical literature. The average wholesale prices of the most commonly used diuretics in pediatric patients differ appreciably. Table 1 lists specific wholesale prices for commonly used diuretics as reported through our wholesaler at initiation of the study. Scant data have been reported to support the use of high-cost agents over less-expensive options for pediatric patients in the cardiovascular ICU. Due to the anecdotally high use of i.v. chlorothiazide and i.v. ethacrynic acid in the study institution, the pharmacy
department and the pediatric cardiovascular surgery team developed and implemented a diuretic stewardship program in an attempt to curtail the prescribing patterns for expensive diuretics while avoiding adverse effects on patient care. The evaluation and validation of this program could lead to more cost-effective diuretic therapy by promoting the maximized use of inexpensive loop diuretics and oral thiazide diuretics before i.v. chlorothiazide in pediatric patients undergoing cardiothoracic surgery. The primary objective of this study was to evaluate the effectiveness of a diuretic stewardship program in a pediatric cardiovascular ICU in reducing pharmacy drug expenditures related to the use of i.v. chlorothiazide and i.v. ethacrynic acid. The secondary objectives were to assess the impact of the diuretic stewardship program on surrogate markers of in-hospital morbidity and to evaluate the appropriate use of i.v. chlorothiazide and i.v. etha crynic acid before and after program inception. Methods A diuretic stewardship program was implemented on the pediatric cardiovascular surgery service at Riley Hospital for Children in Indianapolis, Indiana, on January 1, 2013. Information regarding the appropriate indications, dosing, and
Table 1.
Wholesale Prices of Diuretics Drug
Strength
Price (U.S. Dollars)a
Bumetanide 2.5 mg/10 mL (i.v.), 0.5 mg (oral) $0.18/vial, $0.34/tablet Ethacrynic acid 50 mg (i.v.) $905.00/vial Furosemide 20 mg/2 mL (i.v.), $0.10/mL, 10 mg/mL (oral solution) $1.05/vial Chlorothiazide 500 mg (i.v.), 500 mg (oral) $348.00/vial, $1.24/tablet Hydrochlorothiazide 12.5 mg (oral) $0.20/capsule Metolazone 2.5 mg (oral) $1.48/tablet As of August 2013.
a
1048
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costs of various diuretic agents was distributed via e-mail to all pediatric cardiac intensivists (n = 8), cardiovascular surgeons (n = 3), cardiologists (n = 15), and nurse practitioners (n = 6) who cared for patients on the cardiovascular surgery service. After this information was provided, pharmacy interventions were performed by the pediatric critical care clinical pharmacy specialists for i.v. chlorothiazide and i.v. ethacrynic acid doses that did not meet the criteria for appropriate use. Although interventions were not made on every dose ordered, these interventions consisted of real-time guidance and feedback during daily clinical rounds, live or telephonic communication with prescribers, one quarterly update on the progress of the program, and continued education on the use and indications of the various diuretic agents. No changes were made to any order sets or clinical decision support within the computerized prescriberorder-entry system. Appropriate use of i.v. chlorothiazide was defined as any patient receiving one of the following: i.v. furosemide ≥1 mg/kg every six hours, continuous i.v. furosemide infusion ≥0.2 mg/kg/hr, any strength of i.v. bumetanide every six hours, or any strength of a continuous i.v. bumetanide infusion. A weight-based dose for bumetanide was not specified due to lack of consensus at our institution regarding equivalent dose ranges when compared with furosemide. I.V. ethacrynic acid was considered appropriate only in patients with a documented sulfonamide allergy. This study was reviewed and approved by the Indiana University institutional review board. Six months after the diuretic stewardship program was implemented, the pharmacy database and electronic medical records were retrospectively queried to identify patients for inclusion from January 1 through June 30 in both 2012 and 2013. All patients admitted to the
NOTES Diuretic stewardship program
pediatric ICU and cared for by the cardiovascular ICU service after cardiac surgery during the study period were included. Patients admitted to the pediatric ICU and cared for by the pediatric critical care service were excluded. A detailed review of the pharmacy database and medical records was performed for each patient to determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. Data were analyzed with the Mann– Whitney U test. The a priori level of significance was 0.05. Results The number of patients undergoing cardiovascular surgery was relatively consistent during the first two quarters of 2012 and 2013 (149 and 163, respectively). After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of $91,398 in expenditures on these diuretics over the six-month study period and an estimated annual savings of over $182,000 (Table 2). Although appropriate prescribing patterns of i.v. chlorothiazide improved by 4.5%, the number of patients and the duration of use were notably attenuated, leading to an 85% reduction ($58,327) in money spent on inappropriate doses of i.v. chlorothiazide and ethacrynic acid combined. In addition, the median number of days using a ventilator (one day in 2012 and 2013) and the length of ICU stay (four days in 2012 versus three days in 2013) did not differ significantly during the study period. Discussion Combination diuretic therapy with thiazide diuretics is used to augment loop diuretic therapy and to overcome diuretic resistance in
cardiac surgery patients.5,9 Despite the prevalence of this practice, data linking this practice to improved outcomes are limited. Jentzer and colleagues5 reviewed data on the use of combination diuretic therapy in adult heart failure patients. Their review covered the entire adult heart failure literature base but involved only about 300 patients in 50 reports. In 2013, Ng and colleagues6 conducted a retrospective study, which remains the single most robust study to date, reviewing single and combination diuretic therapy in 242 adult patients with acute heart failure. This report compared patients who initially received intermittent furosemide therapy that was later changed to continuous-infusion furosemide, a combination of furosemide and metolazone, or continuous-infusion bumetanide. The authors found all three of the escalated regimens resulted in higher urine output compared to intermittent furosemide therapy. Additionally, they concluded that patients who received furosemide plus metolazone and those who received continuous-infusion bumetanide had a better response
compared to continuous-infusion furosemide. Although the body of literature regarding combination diuretic therapy among adult patients remains sparse, combination diuretic therapy reports for pediatric patients are even rarer and mostly limited to small retrospective studies and case reports in noncardiacsurgery patients.5,6,9-12 Although this investigation primarily focused on the pharmacoeconomic impact of diuretic stewardship, to our knowledge it is the first to link outcomes and combination diuretic therapy in pediatric patients. Smith and colleagues13 recently reported dramatic increases in healthcare resources used for 13,156 neonatal congenital heart patients in 2005–11. They reported an increase in total pharmacy charges of 16% per patient case (from $39,441 to $45,743) and found i.v. chlorothiazide to be one of the top two drugs accounting for the increase. I.V. chlorothiazide use increased from 26% of patients in 2005 to 37% of patients in 2011, resulting in a 755% increase in charges per patient case (from $886 in 2005 to $7,582 in 2011).
Table 2.
Characteristics of I.V. Chlorothiazide and Ethacrynic Acid Use Among Patients Undergoing Cardiovascular Surgery in 2012 and 2013 Variable
2012 (n = 149)
2013 (n = 163)
I.V. chlorothiazide Patients, no. (%) 53 (35.5) 30 (18.4) Doses, no. 716 185 Doses/patient 4.81 1.13 Appropriate doses, no. (%) 471 (65.8) 130 (70.3) Cost, $ 75,111 23,260 Cost of inappropriate doses, $ 25,688 6,908 I.V. ethacrynic acid Patients, no. (%) 29 3 Doses, no. 51 4 Doses/patient 0.34 0.02 Appropriate doses, no. (%) 0 0 Cost of inappropriate doses, $ 42,913 3,366 Total cost, $ 118,024 26,626 Total cost of inappropriate doses, $ 68,601 10,274
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NOTES Diuretic stewardship program
In addition, few data exist on the use of i.v. ethacrynic acid as a first-line loop diuretic outside of the clinical scenario of potential allergic cross-reactivity in patients with a documented sulfonamide allergy. Although the use of i.v. ethacrynic acid meaningfully decreased during our study period, the rate of appropriate use remained unchanged at 0%. We believe the decreased use of this drug combined with the cost savings of nearly $40,000 in a six-month period highlights the success of this program, despite the continued inappropriate use of ethacrynic acid after the study interventions. We believe that the inappropriate use of ethacrynic acid remained 100% in both study periods due to the low rate (0%) of patients in the study with a documented sulfonamide allergy, combined with the fact that not all doses were accompanied with a formal educational intervention by the clinical pharmacist. More study is needed to evaluate the role of ethacrynic acid as a first-line diuretic before using inexpensive options such as furosemide and bumetanide in patients without a sulfonamide allergy. With the lack of data supporting the use of first-line i.v. ethacrynic acid or the addition of i.v. chlorothiazide before maximizing loop diuretic therapy, it may be clinically and pharmacoeconomically appropriate to limit the use of these agents to certain clinical scenarios. The cost of i.v. chlorothiazide to institutions is approximately 360 times more than that of i.v. furosemide. Compared with hydrochlorothiazide and metolazone, i.v. chlorothiazide is 2500 and 220 times more expensive, respectively.14 Due to these extreme differences in institutional drug acquisition costs, we believe it is reasonable to maximize inexpensive loop diuretic therapy and use oral hydrochlorothiazide or metolazone before using i.v. chlorothiazide. Although we observed only a marginal increase in the percentage 1050
of appropriately prescribed doses of i.v. chlorothiazide after implementation of the stewardship program, the absolute number of inappropriately prescribed doses was greatly reduced due to the dramatic decrease in the overall utilization of i.v. chlorothiazide in the cardiovascular ICU, despite the increased number of surgeries in 2013. The diuretic stewardship program successfully decreased the use of i.v. chlorothiazide and i.v. ethacrynic acid in all patients admitted to the cardiovascular ICU, which was the goal. We believe this was the result of the education provided regarding the extreme cost differential between i.v. chlorothiazide and i.v. ethacrynic acid and other inexpensive i.v. and oral diuretic options. We believe prescribers were much less willing to use i.v. chlorothiazide and i.v. ethacrynic acid than they were before the program’s interventions, resulting in decreased overall utilization of i.v. chlorothiazide by 3.68 doses per patient case and i.v. ethacrynic acid by 0.32 dose per patient case in nearly identical patient populations from 2012 through 2013. The savings realized by the hospital for i.v. chlorothiazide and i.v. ethacrynic acid during the six-month study period exceeded $90,000 while the ICU length of stay and days on mechanical ventilation remained the same between study periods, alleviating concerns that the cost saving realized from this stewardship measure would be negated by increased expenditures elsewhere or decreased quality of care. During a time in which institutions aim to cut expenses, a diuretic stewardship program is an attractive option for hospitals to consider in an effort to cut costs without compromising patient care. An important aspect of the development and implementation of a successful diuretic stewardship program, however, is sustainability. Antimicrobial stewardship programs have reported that sustainability is most
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attainable when both passive (e.g., education via e-mail or newsletters) and active (e.g., one-on-one interventions) approaches to stewardship are exercised.15 We believe such strategies were paramount to the success of the program and will be essential to its future sustainability. Our study had some limitations. Although we are confident that all cases and drug utilization patterns were captured during data collection, the retrospective nature of the study limited the ability to make observations with the precision and granularity of a prospective study. We attempted to account for potential variation in patient populations by studying comparable time periods during which the variation in patient population would be minimized; January through June encompasses a large portion of the respiratory viral season, and early summer brings high numbers of surgeries to our institution. Although the number of patients included in this study was relatively small, to our knowledge it represents the only collection of pediatric patients to date for whom a diuretic stewardship program has been used. In addition, this is the largest report of i.v. chlorothiazide use in pediatric cardiovascular surgery patients to date. It is our hope that the results of this study will motivate other centers to adopt similar practices in an effort to provide high-quality healthcare while simultaneously incorporating optimal pharmacoeconomic practices for pediatric cardiovascular surgery patients. Future steps to further optimize this program will include the incorporation of clinical decision support within the computerized prescriber-order-entry system. Conclusion Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as
NOTES Diuretic stewardship program
ventilator days and length of stay in a pediatric cardiovascular ICU. References 1. Kozik DJ, Tweddell JS. Characterizing the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. 2006; 81:S2347-54. 2. Jones TJ, Elliott MJ. Paediatric CPB: bypass in a high risk group. Perfusion. 2006; 21:229-33. 3. Van der Vorst MM, Ruys-Dudok van Heel I, Kist-van Holthe JE et al. Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery. Intensive Care Med. 2001; 27:711-5. 4. Schoemaker RC, van der Vorst MM, van Heel IR et al. Development of an optimal furosemide infusion strategy in infants with modeling and simulation. Clin Pharmacol Ther. 2002; 72:383-90. 5. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010; 56:1527-34. 6. Ng TM, Konopka E, Hyderi AF et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther. 2013; 18:345-53. 7. American Society of Health-System Pharmacists. ASHP guidelines on medication cost management strategies for hospitals and health systems. Am J Health-Syst Pharm. 2008; 65:1368-84. 8. Centers for Medicare and Medicaid Services. National health expenditure projections 2012-2022: forecast summary. www.cms.gov/Research-StatisticsData-and-Systems/Statistics-Trends-andReports/NationalHealthExpendData/ downloads/proj2012.pdf (accessed 2014 Nov 6). 9. Cachero SD, Lofland G, Springate JE, Feld LG. Combination of metolazone and furosemide in the treatment of edema in the first month of life. Child Nephrol Urol. 1990; 10:161-3. 10. Arnold WC. Efficacy of metolazone and furosemide in children with furosemideresistant edema. Pediatrics. 1984; 74:872-5. 11. Garin EH. A comparison of combinations of diuretics in nephrotic edema. Am J Dis Child. 1987; 141:769-71. 12. Segar JL, Robillard JE, Johnson KJ et al. Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia. J Pediatr. 1992; 120:966-73. 13. Smith AH, Gay JC, Patel NR. Trends in resource utilization associated with the inpatient treatment of neonatal congenital heart disease. Congenit Heart Dis. 2014; 9:96-105. 14. Society of Critical Care Medicine. Drug shortage alert: November 15, 2012. www. learnicu.org/Lists/Web%20Contents/ Attachments/9640/DrugShortageAlert, %2011.15.12.pdf 15. Tamma PD, Cosgrove SE. Antimicrobial stewardship. Infect Dis Clin North Am. 2011; 25:245-60.
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