C L I N I C A L F O C U S : C A R D I O M E TA B O L I C H E A LT H , A N D P U L M O N A RY A N D VA S C U L A R M A N A G E M E N T
Is Glycemic Control of the Critically Ill CostEffective?
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DOI: 10.3810/hp.2014.10.1142
James S. Krinsley, MD, FCCM, FCCP 1 Director of Critical Care, Stamford Hospital, Clinical Professor of Medicine, Columbia University College of Physicians and Surgeons, Stamford, CT 1
Abstract: Intensive monitoring of blood glucose levels and treatment of hyperglycemia have been associated with significant improvements in morbidity and mortality in the critically ill. In contrast to the large prospective and observational body of data relating glycemic control and clinical outcomes, the financial impact of glycemic control implementation has not been as well described. This article details data from interventional trials of intensive insulin therapy; investigations that relate dysglycemia to morbidity, particularly intensive care unit (ICU)– acquired infections and increased ICU length of stay; and evaluations of the attributable cost of nosocomial infection in order to construct a sensitivity analysis of the net economic impact of glycemic control. It concludes that glycemic control is associated with positive financial outcomes, even using very conservative assumptions, and provides the reader with an automated spreadsheet to estimate the financial implications of glycemic control using assumptions based on locally derived data. Keywords: glucose control; intensive care unit; economic analysis; hospital-acquired infection; length of stay
Introduction
Correspondence: James S. Krinsley, MD, FCCM, FCCP, 190 West Broad Street, Stamford, CT 06902. Tel: 203-348-2437 Fax: 203-276-7243 E-mail: [email protected]
The modern era of glycemic control in the critically ill began in Portland, Oregon in the late 1980s, with Dr Anthony Furnary’s intensive treatment of hyperglycemia in patients with diabetes undergoing cardiovascular surgery.1 However, interest in this treatment paradigm blossomed after the 2001 publication of the single-center randomized controlled trial of intensive insulin therapy conducted in 1548 mechanically ventilated surgical intensive care unit (ICU) patients in Leuven, Belgium.2 A rich literature has described the subsequent series of interventional trials and large body of observational data regarding attempts to control blood glucose (BG) in various acutely and critically ill populations, and the relationship of the 3 domains of glycemic control—hyperglycemia, hypoglycemia, and glucose variability—to outcomes in patients with and without diabetes mellitus.3–6 Notably, only the first Leuven study2 and a large before-and-after study conducted subsequently at Stamford Hospital7 showed substantial improvements in mortality and morbidity with intensive BG monitoring and treatment of hyperglycemia. Subsequently published interventional trials of intensive insulin therapy reported only modest benefit,8 were stopped prematurely because of high rates of severe hypoglycemia9 or failure to maintain targeted time in BG range,10 or, in the case of the largest trial, Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR), higher 90-day mortality in patients treated in the intensive arm.11
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James S. Krinsley
In summary, the clinical benefits of intensive insulin therapy have been demonstrated most convincingly in critically ill surgical patients. Notably, however, the varying results of the interventional trials were confounded by suboptimal glycemic control: high rates of hypoglycemia and low time in targeted BG range in the interventional arms. In contrast to this relatively large body of literature on the clinical effects of dysglycemia and the attempts to control it in the critically ill, much less attention has been devoted to the financial implications of glycemic control in the critically ill.12 This review analyzes data from interventional and observational investigations to address whether glycemic control in the critically ill is cost-effective. It includes evidence from 2 interventional trials of intensive insulin therapy, data linking dysglycemia to nosocomial infection and ICU and hospital length of stay (LOS), the attributable costs of nosocomial infections, an evaluation of the direct costs of BG monitoring and treatment, and a sensitivity analysis, in order to reach a strongly affirmative conclusion.
Methods
A comprehensive review of the literature was performed to identify investigations that evaluated the costs associated with glycemic control in critically ill patients; the relationship between disturbances in glucose control and resource use, including ICU LOS and infections; and costs attributable to hospital-acquired infection. A PubMed search identified relevant work, and review of the reference lists of these published manuscripts identified other studies of potential interest. Finally, a model was constructed to evaluate the overall costs and savings associated with glycemic control. Some of the data used in this model were obtained from the Stamford Hospital Pharmacy Department; other parameters were abstracted from relevant literature.
Results Evidence From Interventional Trials of Intensive Insulin Therapy in Critically Ill Patients
The first randomized controlled trial of intensive insulin therapy in a critically ill population resulted in a 37% reduction in mortality and a 40% to 50% reduction in various important morbidities, such as bloodstream infections, critical illness polyneuropathy, and the need for renal replacement therapy.2 The Leuven investigators subsequently performed an economic analysis of their trial,13 comparing resource use of the intensively and conventionally treated cohorts. They evaluated the costs associated with ICU LOS; days of 54
mechanical ventilation; use of renal replacement therapy; use of specific medications and blood transfusions; and the cost of BG monitoring. They calculated a net cost savings of 2638 euros per patient, driven in large part by the difference in ICU LOS between the 2 groups (mean [SEM]), 8.6 [0.5] vs 6.6 [0.4] days; P = 0.005), but including a significant decrease in the cost of the other measured metrics among patients in the interventional arm of the trial, offset only partially by the increased cost of BG monitoring and treatment. The first confirmation of the Leuven trial was published in 2004.7 The Stamford trial included 1600 patients in a “before and after” design and was notable for a 29% reduction in mortality in the patients treated in the interventional period, and a significant decrease in blood transfusions and the need for renal replacement therapy. A post hoc economic analysis was published the same month as the Leuven health resource study, and reached similar conclusions.14 This study included the cost of ICU and floor days and of mechanical ventilation, and a comprehensive assessment of all laboratory, pharmacy, and radiology costs, balanced against an evaluation of the costs of BG monitoring and treatment, and concluded that the net cost savings was $1580 per patient. Finally, Sadhu et al15 performed a single-center, multiICU study that compared intensive insulin therapy, targeting BG 80 to 110 mg/dL, with usual care (BG target set at the discretion of the intending physician), using a before-and-after design, in 6719 patients admitted to 5 interventional and 4 comparison ICUs at the University of California Los Angeles between 2003 and 2005. The intervention was associated with a statistically significant reduction in ICU LOS (median, 1.19 days; interquartile range, 0.43–1.93) and strong trends toward a reduction in ICU and total direct costs.
Evidence Linking Dysglycemia to Nosocomial Infection and ICU LOS
Considerable evidence links perturbations in glycemic control during acute and critical illness, in particular, hyperglycemia and hypoglycemia, and morbidity, including the risk of nosocomial infection and increased ICU and hospital LOS. Furnary and Wu1 described the outcomes of 5510 patients with diabetes undergoing cardiovascular surgery at a single center between 1987 and 2005. They created a metric, “3-BG,” that represented the mean BG of all tests performed on the day of surgery (DOS) and on postoperative days (PODs) 1 and 2. Mortality was 1% among patients with 3-BG 150 mg/dL and increased to nearly 14% among patients with 3-BG > 250 mg/dL. Moreover, each 50 mg/dL increase in 3-BG was associated with a 1.73-fold increase
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Cost-Effectiveness of Glycemic Control
in the odds ratio for the development of deep sternal wound infection (DSWI). In addition, each 50 mg/dL increase in 3-BG was associated with: 2.2-fold increase in transfusion requirement (P 0.0001); 1.2-fold increase in risk of postoperative atrial fibrillation (P 0.001); 1.6-fold increase in inotropic requirement 48 hours (P 0.03); 1.2-fold increase in infections other than DSWI (P 0.02); and, finally, a 1-day increase in ICU LOS. These investigators estimated that, largely because of its effect on reduction in LOS and the incidence of DSWI, the implementation of intensive glycemic control was associated with a savings of $5580 per patient treated. Other investigations describe an independent association of hyperglycemia with increased risk of nosocomial infection. Yendamuri et al16 analyzed 738 patients admitted to a single level 1 trauma center, stratifying patients based on admission BG or 135 mg/dL. Admission hyperglycemia was independently associated with the subsequent development of urinary tract infection (odds ratio [OR] 3.3; 95% CI, 1.2–8.8) and pneumonia (OR, 2.8; 95% CI, 1.0–8.0), and mortality and ICU and hospital LOS. Kwon et al17 performed a retrospective analysis of 11 633 patients admitted to 47 hospitals in Washington state for elective colorectal or bariatric surgery in order to evaluate the association of any BG 180 mg/dL with adverse outcomes. Hyperglycemia was associated with increased risk of infection, reoperative interventions, and death in patients with and without diabetes mellitus. In patients with even a single BG 180 mg/dL on DOS, POD 1 or 2, POD 1 and 2, the investigators reported ORs of 1.7, 2.1, and 3.1, respectively, for postoperative infection. Finally, in 447 patients undergoing elective hepatobiliary or pancreatic surgery, Okabayashi et al18 recently reported the results of a single-center randomized controlled trial of 2 BG targets, 80 to 110 mg/dL versus 140 to 180 mg/dL, the target ranges of the interventional and control arms of the NICE-SUGAR trial.11 They used a “closed loop” computerized insulin monitoring and delivery system, achieving a very high percentage of time in targeted range in both groups and no hypoglycemia (BG 70 mg/dL) in either group. The primary outcome, surgical site infection, occurred in 9.8% of the patients in the moderate BG arm and 4.1% of the patients in the tight BG arm (P = 0.028). In addition, they found a lower incidence of postoperative pancreatic fistula after pancreatic resection (P = 0.040) and shorter hospital LOS (P = 0.017) among patients in the tight cohort. A more limited literature search identified an independent association of hypoglycemia with morbidity in critically ill populations. Egi et al19 evaluated 4946 patients admitted to
2 Australian mixed medical-surgical ICUs between 2000 and 2004, with a BG target range of 108 to 180 mg/dL. Compared with patients with a minimum BG during ICU stay of 72 to 81 mg/dL, those with minimum BG values of 54 to 63, 45 to 54, 36 to 45, and 36 mg/dL had ORs for nosocomial infection of 2.2, 3.4, 1.8, and 3.1, respectively. Mild hypoglycemia was also independently associated with increased risk of death and increased ICU LOS. Mild hypoglycemia was associated with increased ICU LOS in an investigation including observational data from Stamford Hospital and the Academic Medical Center in Amsterdam, and prospective data from the Glucontrol study of intensive insulin therapy.20 In this heterogeneous group of 6410 patients, median ICU LOS was 3.0 versus 1.8 days (P 0.0001) for those with and without a single BG value 70 mg/dL during ICU stay; these results were consistent when patients were stratified by survivor status or severity of illness.
Attributable Costs of Hospital-Acquired Infections
Nosocomial infections are expensive. The Association for Professionals in Infection Control and Epidemiology published an analysis of the attributable cost of individual hospital-acquired infections (HAIs).21 Their methodology included aggregation of the cost of all services required for each class of infection, including the excess LOS. These costs ranged from $5904 for urinary tract infection to $32 199 for central line–associated blood stream infection. A report published by the Centers for Disease Control and Prevention in 2009 also estimated the cost associated with each class of nosocomial infection, reaching similar conclusions, but further provided an estimate of the overall direct patient costs of all HAIs.22 These aggregated low and high estimates for a single HAI, in 2007 US dollars, were $20 549 and $25 903, respectively.
Cost of Glycemic Control
The economic analysis of the first Leuven trial concluded that the cost of therapy, including medication, intravenous tubing, fluid, and monitoring, was 144 euros per patient.13 This investigation was performed between 2000 and 2001; the mean ICU LOS of the patients in the interventional arm was 6.6 days, yielding an approximate cost of 22 euros per day. Accounting for a conservative rate of 4% price inflation per year, and converting to dollars at a rate of 1 euro = $1.35, this corresponds to a cost of $51 per day per patient in 2014 US dollars. The economic analysis of the Stamford trial, performed between 2002 and 2003, provides an estimated
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cost of $52 500 for 3586 patient days in the interventional group, or approximately $15 per day per patient. Accounting for a conservative rate of inflation of 4% per year, this corresponds with a cost of $24 per day per patient in 2014 US dollars. However, these costs may underestimate the cost of BG monitoring. The 2 primary modes of BG monitoring in current clinical use are blood gas analyzers and bedside glucometers. The cost of BG monitoring using a blood gas analyzer includes the cost of the solute used to perform an individual test (estimated to be $3.78 per test, based on current purchasing cost data from the Stamford Hospital pharmacy) and the cost of the analyzer itself, estimated to be $15 000. Assuming this cost per test, the purchase of 2 blood gas analyzers for the ICU, and a BG testing interval of every 2 hours (which is notably significantly more frequent than was performed by any of the 9 centers in a recently published international observational study6), the cost of monitoring using blood gas analyzers is estimated to be $52.86 per day per patient ($45.36 attributed to the cost of the analyzer cartridges, and $7.50 attributed to the cost of 2 analyzers spread over 4000 patient days). The cost of BG monitoring using glucometers and strips includes the cost of the strips (estimated to be $0.43 per test, based on current purchasing cost data from the Stamford Hospital pharmacy), and the cost of the glucometer, estimated to be $500. Assuming this cost per test, the purchase of 3 glucometers for the ICU, and a BG testing interval of every 2 hours, the cost of monitoring using glucometers and strips is estimated to be $5.54 per day per patient ($5.16 attributed to the cost of the strips and $0.38 attributed to the cost of the 3 glucometers spread over 4000 patient days). In both cases, a liberal estimate of the cost of intravenous tubing and insulin is $50 per day per patient. These estimates do not account for nursing and/or technician time spent performing BG monitoring and treatment, conservatively ranging from 6 to 10 minutes per test for blood gas analyzers and 3 to 5 minutes per test for glucometers.
Sensitivity Analysis: Costs and Savings Attributable to Glycemic Control Assumptions
For the purposes of this sensitivity analysis, 1000 admissions per year to the ICU were assumed, with a mean ICU LOS of 4 days, yielding 4000 patient days per year. Every patient will undergo BG monitoring and treatment every day, with measurement intervals of every 1 hour and every 2 hours entered into the model. The cost differential between an 56
“ICU bed day” and a “floor bed day” is conservatively estimated to be $1000 per day. The attributable cost of an ICU-acquired infection is $25 000. The baseline incidence of ICU-acquired infection is conservatively estimated to be 10% of the patients. An automated spreadsheet is included as a Supplementary File that allows the reader to change the financial assumptions of this analysis to reflect locally derived data.
Costs Table 1 summarizes the cost of glycemic control, including the costs associated with insulin treatment and BG monitoring, based on information received from the pharmacy department at Stamford Hospital. (As an overview of glycemic control practice at Stamford Hospital, the current blood glucose target range for patients admitted to the ICU is 90–120 mg/dL. Monitoring is performed using glucometers [AccuChek Inform 2, Roche Diagnostics, Indianapolis, Indiana] and strips. Blood glucose values 180 mg/dL twice in a row trigger the initiation of IV infusion of insulin and monitoring frequency of q1h. Blood glucose values between 121 and 179 mg/dL are treated with subcutaneous insulin aspart, administered q3h as needed. Insulin dosing is nursedriven. The minimum monitoring frequency for all patients is q3h. Insulin glargine is used to supply a portion of the insulin requirement in some patients whose condition has stabilized and are receiving enteral nutrition. Nutritional support is Table 1. Cost of Insulin Therapy and Glucose Monitoringa Treatment Insulinb Bag of 100 mL NS (for infusion of insulin) Tubing for intravenous infusion Monitoring
$7.20 $1.70 $0.64
Cartridge for blood gas analyzer (cost per test)c q1h q2h q3h Strips for glucometerd
$90.67 $45.36 $30.24
q1h q2h q3h
$10.32 $5.16 $3.44
Current costs obtained from the pharmacy department at Stamford Hospital. Costs are per patient, per day. b Cost of insulin is for continuous regular infusion at 4 U/h for 24 hours ($1.23), or subcutaneous therapy including 30 U/d of insulin aspart and 30 U/d of insulin glargine ($7.20). The higher number is chosen for this estimate. Each insulin concentration is 1 mL = 100 U. Regular insulin (Humulin R): $12.30 per 10-mL vial Insulin aspart: $45.02 per 10-mL vial Insulin glargine: $195.02 per 10-mL vial c Cost of blood gas analyzer cartridge: $1700 for 450 tests = $3.78 per test. d Cost of 50 strips: $21.34 = $0.43 per test. Abbreviation: NS, normal saline. a
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Cost-Effectiveness of Glycemic Control
begun within 24−48 hours in most patients admitted to the ICU, nearly predominantly via the enteral route.) Treatment costs include the cost of the different insulin preparations used and the cost of intravenous tubing and intravenous infusion bags. Two modes of monitoring—blood gas analyzers and glucometers—are compared. In the former case, costs include the purchase of the blood gas analyzers (2 per ICU) and the cost of the cartridge used for analysis. In the latter case, this includes the purchase cost of glucometers (3 per ICU) and the cost of the strips.
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Savings Savings result from reductions in ICU LOS and the occurrence of ICU-acquired infections. Figure 1 illustrates the impact of a 5%, 10%, 15%, and 20% reduction in these parameters, using a range of attributable costs for an ICUacquired infection, in an ICU with a baseline incidence of 10% of patients developing an ICU-acquired infection.
Discussion
This article evaluates available literature to reach conclusions about the beneficial financial impact of implementation of glycemic monitoring and treatment of hyperglycemia in critically ill patients. An important limitation is that only the first Leuven study2 and a large before-and-after study conducted subsequently at Stamford Hospital7 showed
substantial improvements in mortality and morbidity with intensive BG monitoring and treatment of hyperglycemia; data from these 2 investigations also demonstrated substantial cost savings. Other investigations document increased morbidity, particularly ICU-acquired infections and increased ICU LOS, associated with hyperglycemia and hypoglycemia. The substantial cost of nosocomial infections is addressed in other recent work.21,22 Contemporary costs of 2 modalities for BG monitoring, blood gas analyzer and glucometer, are entered into a comprehensive sensitivity analysis to yield an estimate of the net financial impact of glycemic control implementation using a 10% baseline incidence of ICUacquired infection. The cost of glycemic control was estimated assuming every-1-hour and every-2-hour monitoring with glucometers was performed and the cost of strips was $82 780 and $62 140, respectively, for an ICU with 1000 admissions per year, mean ICU LOS of 4 days, and 100% of patient days included. Under the same assumptions, the cost of glycemic control using every-1-hour and every-2-hour monitoring with blood gas analyzers was estimated to be $432 880 and $251 440, respectively. Even with a more conservative estimate of benefit—a 5% reduction in ICU-acquired infection and ICU LOS in an ICU with a very low preimplementation 5% incidence of ICU-acquired infection—glycemic control is associated with a savings of $262 500, yielding a net
Figure 1. Savings and costs associated with glycemic control.
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James S. Krinsley
financial benefit of $11 060 in the model using every-2-hour monitoring with a blood gas analyzer, and $200 360 in the model using every-2-hour monitoring with strips and glucometers. With moderate benefit—a 10% reduction in ICU-acquired infection and ICU LOS—in a unit with 10% preimplementation incidence of HAI, the savings increase substantially to $650 000, yielding strong net financial benefit under each of the scenarios. For an ICU with a 15% preimplementation incidence of HAI that achieves a 15% reduction in ICU-acquired infection and ICU LOS, the savings increase to $1 162 500, representing a substantially higher net financial benefit. Finally, these data were accumulated in the last 10 to 15 years of experience with glycemic control, using currently available technologies. The sensitivity analysis includes monitoring frequencies that are not typically achieved in contemporary clinical practice.6 Increased monitoring frequency will almost certainly improve time in the targeted BG range,23 and offers the promise of improved clinical outcomes for critically ill patients.18
Conclusion
Abnormalities in glucose control, especially hyperglycemia and hypoglycemia, are associated with mortality and substantial morbidity in the critically ill. The financial burden of nosocomial infection and increased ICU and hospital length of stay is considerable. A detailed sensitivity analysis concludes that efforts to ameliorate dysglycemia have a beneficial economic impact.
Conflict of Interest Statement
James S. Krinsley, MD, FCCM, FCCP, discloses a relationship as a consultant and advisory board member with Edwards Life Sciences, OptiScan Biomedical, and Medtronic.
References 1. Furnary AP, Wu Y. Clinical effects of hyperglycemia in the cardiac surgery population: the Portland Diabetic Project. Endocr Pract. 2006;12(Suppl 3):22–26. 2. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359–1367. 3. Ichai C, Preiser JC. International recommendations for glucose control in adult non diabetic critically ill patients. Crit Care. 2010;14(5):R166. 4. Kavanagh BP, McCowen KC. Clinical practice. Glycemic control in the ICU. N Engl J Med. 2010;363(26):2540–2546.
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5. Krinsley JS. Should guidelines for glycemic control of the critically ill be individualized?: weighing the evidence from randomized and observational investigations. Hosp Pract (1995). 2014;42(2):14–22. 6. Krinsley JS, Egi M, Kiss A, et al. Diabetic status and the relationship of the three domains of glycemic control to mortality in critically ill patients: an international multi-center cohort study. Crit Care. 2013;17(2):R37. 7. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic Proc. 2004;79(8):992–1000. 8. van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–461. 9. Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–139. 10. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009;35:1738–1748. 11. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283–1297. 12. Scurlock C, Raikhelkar J, Mechanick JI. The economics of glycemic control in the ICU in the United States. Curr Opin Clin Nutr Metab Care. 2011;14:209–212. 13. van den Berghe G, Wouters P, Kesteloot K, Hilleman DE. Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med. 2006;34(3):612–616. 14. Krinsley JS, Jones RL. Cost analysis of intensive glycemic control in critically ill adult patients. Chest. 2006;129(3):644–650. 15. Sadhu AR, Ang A, Ingram-Drake L, Martinez DS, Hsueh WA, Ettner SL. Economic benefits of intensive insulin therapy in critically ill patients: the targeted insulin therapy to improve hospital outcomes (TRIUMPH) project. Diabetes Care. 2008;31:1556–1561. 16. Yendamuri S, Fulda GJ, Tinkoff GH. Admission hyperglycemia as a prognostic indicator in trauma. J Trauma. 2003;55(1):33–38. 17. Kwon S, Thompson R, Dellinger P, Yanez D, Farrohki E, Flum D. Importance of perioperative glycemic control in general surgery: a report from the Surgical Care and Outcomes Assessment Program. Ann Surg. 2013;257(1):8–14. 18. Okabayashi T, Shima Y, Sumiyoshi T, et al. Intensive versus intermediate glucose control in surgical intensive care unit patients. Diabetes Care. 2014;37(6):1516–1524. 19. Egi M, Bellomo R, Stachowski E, et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc. 2010;85(3):217–224. 20. Krinsley JS, Schultz MJ, Spronk PE, et al. Mild hypoglycemia is strongly associated with increased intensive care unit length of stay. Ann Intensive Care. 2011;1:49. 21. Murphy D, Whiting J. Dispelling the myths: the true cost of healthcareassociated infections. https://www.premierinc.com/safety/topics/ guidelines/downloads/09-hai-whitepaper.pdf. Accessed September 7, 2014. 22. Douglas SR II. The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. Centers for Disease Control and Prevention Web site. http://stacks.cdc.gov/view/cdc/11550. Accessed July 31, 2014. 23. Boyd JC, Bruns DE. Effects of measurement frequency on analytical quality required for glucose measurements in intensive care units: assessments by simulation models. Clin Chem. 2014;60:644–650.
© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
Is Glycemic Control of the Critically Ill CostEffective?
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DOI: 10.3810/hp.2014.10.1142
James S. Krinsley, MD, FCCM, FCCP 1 Director of Critical Care, Stamford Hospital, Clinical Professor of Medicine, Columbia University College of Physicians and Surgeons, Stamford, CT 1
Abstract: Intensive monitoring of blood glucose levels and treatment of hyperglycemia have been associated with significant improvements in morbidity and mortality in the critically ill. In contrast to the large prospective and observational body of data relating glycemic control and clinical outcomes, the financial impact of glycemic control implementation has not been as well described. This article details data from interventional trials of intensive insulin therapy; investigations that relate dysglycemia to morbidity, particularly intensive care unit (ICU)– acquired infections and increased ICU length of stay; and evaluations of the attributable cost of nosocomial infection in order to construct a sensitivity analysis of the net economic impact of glycemic control. It concludes that glycemic control is associated with positive financial outcomes, even using very conservative assumptions, and provides the reader with an automated spreadsheet to estimate the financial implications of glycemic control using assumptions based on locally derived data. Keywords: glucose control; intensive care unit; economic analysis; hospital-acquired infection; length of stay
Introduction
Correspondence: James S. Krinsley, MD, FCCM, FCCP, 190 West Broad Street, Stamford, CT 06902. Tel: 203-348-2437 Fax: 203-276-7243 E-mail: [email protected]
The modern era of glycemic control in the critically ill began in Portland, Oregon in the late 1980s, with Dr Anthony Furnary’s intensive treatment of hyperglycemia in patients with diabetes undergoing cardiovascular surgery.1 However, interest in this treatment paradigm blossomed after the 2001 publication of the single-center randomized controlled trial of intensive insulin therapy conducted in 1548 mechanically ventilated surgical intensive care unit (ICU) patients in Leuven, Belgium.2 A rich literature has described the subsequent series of interventional trials and large body of observational data regarding attempts to control blood glucose (BG) in various acutely and critically ill populations, and the relationship of the 3 domains of glycemic control—hyperglycemia, hypoglycemia, and glucose variability—to outcomes in patients with and without diabetes mellitus.3–6 Notably, only the first Leuven study2 and a large before-and-after study conducted subsequently at Stamford Hospital7 showed substantial improvements in mortality and morbidity with intensive BG monitoring and treatment of hyperglycemia. Subsequently published interventional trials of intensive insulin therapy reported only modest benefit,8 were stopped prematurely because of high rates of severe hypoglycemia9 or failure to maintain targeted time in BG range,10 or, in the case of the largest trial, Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR), higher 90-day mortality in patients treated in the intensive arm.11
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In summary, the clinical benefits of intensive insulin therapy have been demonstrated most convincingly in critically ill surgical patients. Notably, however, the varying results of the interventional trials were confounded by suboptimal glycemic control: high rates of hypoglycemia and low time in targeted BG range in the interventional arms. In contrast to this relatively large body of literature on the clinical effects of dysglycemia and the attempts to control it in the critically ill, much less attention has been devoted to the financial implications of glycemic control in the critically ill.12 This review analyzes data from interventional and observational investigations to address whether glycemic control in the critically ill is cost-effective. It includes evidence from 2 interventional trials of intensive insulin therapy, data linking dysglycemia to nosocomial infection and ICU and hospital length of stay (LOS), the attributable costs of nosocomial infections, an evaluation of the direct costs of BG monitoring and treatment, and a sensitivity analysis, in order to reach a strongly affirmative conclusion.
Methods
A comprehensive review of the literature was performed to identify investigations that evaluated the costs associated with glycemic control in critically ill patients; the relationship between disturbances in glucose control and resource use, including ICU LOS and infections; and costs attributable to hospital-acquired infection. A PubMed search identified relevant work, and review of the reference lists of these published manuscripts identified other studies of potential interest. Finally, a model was constructed to evaluate the overall costs and savings associated with glycemic control. Some of the data used in this model were obtained from the Stamford Hospital Pharmacy Department; other parameters were abstracted from relevant literature.
Results Evidence From Interventional Trials of Intensive Insulin Therapy in Critically Ill Patients
The first randomized controlled trial of intensive insulin therapy in a critically ill population resulted in a 37% reduction in mortality and a 40% to 50% reduction in various important morbidities, such as bloodstream infections, critical illness polyneuropathy, and the need for renal replacement therapy.2 The Leuven investigators subsequently performed an economic analysis of their trial,13 comparing resource use of the intensively and conventionally treated cohorts. They evaluated the costs associated with ICU LOS; days of 54
mechanical ventilation; use of renal replacement therapy; use of specific medications and blood transfusions; and the cost of BG monitoring. They calculated a net cost savings of 2638 euros per patient, driven in large part by the difference in ICU LOS between the 2 groups (mean [SEM]), 8.6 [0.5] vs 6.6 [0.4] days; P = 0.005), but including a significant decrease in the cost of the other measured metrics among patients in the interventional arm of the trial, offset only partially by the increased cost of BG monitoring and treatment. The first confirmation of the Leuven trial was published in 2004.7 The Stamford trial included 1600 patients in a “before and after” design and was notable for a 29% reduction in mortality in the patients treated in the interventional period, and a significant decrease in blood transfusions and the need for renal replacement therapy. A post hoc economic analysis was published the same month as the Leuven health resource study, and reached similar conclusions.14 This study included the cost of ICU and floor days and of mechanical ventilation, and a comprehensive assessment of all laboratory, pharmacy, and radiology costs, balanced against an evaluation of the costs of BG monitoring and treatment, and concluded that the net cost savings was $1580 per patient. Finally, Sadhu et al15 performed a single-center, multiICU study that compared intensive insulin therapy, targeting BG 80 to 110 mg/dL, with usual care (BG target set at the discretion of the intending physician), using a before-and-after design, in 6719 patients admitted to 5 interventional and 4 comparison ICUs at the University of California Los Angeles between 2003 and 2005. The intervention was associated with a statistically significant reduction in ICU LOS (median, 1.19 days; interquartile range, 0.43–1.93) and strong trends toward a reduction in ICU and total direct costs.
Evidence Linking Dysglycemia to Nosocomial Infection and ICU LOS
Considerable evidence links perturbations in glycemic control during acute and critical illness, in particular, hyperglycemia and hypoglycemia, and morbidity, including the risk of nosocomial infection and increased ICU and hospital LOS. Furnary and Wu1 described the outcomes of 5510 patients with diabetes undergoing cardiovascular surgery at a single center between 1987 and 2005. They created a metric, “3-BG,” that represented the mean BG of all tests performed on the day of surgery (DOS) and on postoperative days (PODs) 1 and 2. Mortality was 1% among patients with 3-BG 150 mg/dL and increased to nearly 14% among patients with 3-BG > 250 mg/dL. Moreover, each 50 mg/dL increase in 3-BG was associated with a 1.73-fold increase
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Cost-Effectiveness of Glycemic Control
in the odds ratio for the development of deep sternal wound infection (DSWI). In addition, each 50 mg/dL increase in 3-BG was associated with: 2.2-fold increase in transfusion requirement (P 0.0001); 1.2-fold increase in risk of postoperative atrial fibrillation (P 0.001); 1.6-fold increase in inotropic requirement 48 hours (P 0.03); 1.2-fold increase in infections other than DSWI (P 0.02); and, finally, a 1-day increase in ICU LOS. These investigators estimated that, largely because of its effect on reduction in LOS and the incidence of DSWI, the implementation of intensive glycemic control was associated with a savings of $5580 per patient treated. Other investigations describe an independent association of hyperglycemia with increased risk of nosocomial infection. Yendamuri et al16 analyzed 738 patients admitted to a single level 1 trauma center, stratifying patients based on admission BG or 135 mg/dL. Admission hyperglycemia was independently associated with the subsequent development of urinary tract infection (odds ratio [OR] 3.3; 95% CI, 1.2–8.8) and pneumonia (OR, 2.8; 95% CI, 1.0–8.0), and mortality and ICU and hospital LOS. Kwon et al17 performed a retrospective analysis of 11 633 patients admitted to 47 hospitals in Washington state for elective colorectal or bariatric surgery in order to evaluate the association of any BG 180 mg/dL with adverse outcomes. Hyperglycemia was associated with increased risk of infection, reoperative interventions, and death in patients with and without diabetes mellitus. In patients with even a single BG 180 mg/dL on DOS, POD 1 or 2, POD 1 and 2, the investigators reported ORs of 1.7, 2.1, and 3.1, respectively, for postoperative infection. Finally, in 447 patients undergoing elective hepatobiliary or pancreatic surgery, Okabayashi et al18 recently reported the results of a single-center randomized controlled trial of 2 BG targets, 80 to 110 mg/dL versus 140 to 180 mg/dL, the target ranges of the interventional and control arms of the NICE-SUGAR trial.11 They used a “closed loop” computerized insulin monitoring and delivery system, achieving a very high percentage of time in targeted range in both groups and no hypoglycemia (BG 70 mg/dL) in either group. The primary outcome, surgical site infection, occurred in 9.8% of the patients in the moderate BG arm and 4.1% of the patients in the tight BG arm (P = 0.028). In addition, they found a lower incidence of postoperative pancreatic fistula after pancreatic resection (P = 0.040) and shorter hospital LOS (P = 0.017) among patients in the tight cohort. A more limited literature search identified an independent association of hypoglycemia with morbidity in critically ill populations. Egi et al19 evaluated 4946 patients admitted to
2 Australian mixed medical-surgical ICUs between 2000 and 2004, with a BG target range of 108 to 180 mg/dL. Compared with patients with a minimum BG during ICU stay of 72 to 81 mg/dL, those with minimum BG values of 54 to 63, 45 to 54, 36 to 45, and 36 mg/dL had ORs for nosocomial infection of 2.2, 3.4, 1.8, and 3.1, respectively. Mild hypoglycemia was also independently associated with increased risk of death and increased ICU LOS. Mild hypoglycemia was associated with increased ICU LOS in an investigation including observational data from Stamford Hospital and the Academic Medical Center in Amsterdam, and prospective data from the Glucontrol study of intensive insulin therapy.20 In this heterogeneous group of 6410 patients, median ICU LOS was 3.0 versus 1.8 days (P 0.0001) for those with and without a single BG value 70 mg/dL during ICU stay; these results were consistent when patients were stratified by survivor status or severity of illness.
Attributable Costs of Hospital-Acquired Infections
Nosocomial infections are expensive. The Association for Professionals in Infection Control and Epidemiology published an analysis of the attributable cost of individual hospital-acquired infections (HAIs).21 Their methodology included aggregation of the cost of all services required for each class of infection, including the excess LOS. These costs ranged from $5904 for urinary tract infection to $32 199 for central line–associated blood stream infection. A report published by the Centers for Disease Control and Prevention in 2009 also estimated the cost associated with each class of nosocomial infection, reaching similar conclusions, but further provided an estimate of the overall direct patient costs of all HAIs.22 These aggregated low and high estimates for a single HAI, in 2007 US dollars, were $20 549 and $25 903, respectively.
Cost of Glycemic Control
The economic analysis of the first Leuven trial concluded that the cost of therapy, including medication, intravenous tubing, fluid, and monitoring, was 144 euros per patient.13 This investigation was performed between 2000 and 2001; the mean ICU LOS of the patients in the interventional arm was 6.6 days, yielding an approximate cost of 22 euros per day. Accounting for a conservative rate of 4% price inflation per year, and converting to dollars at a rate of 1 euro = $1.35, this corresponds to a cost of $51 per day per patient in 2014 US dollars. The economic analysis of the Stamford trial, performed between 2002 and 2003, provides an estimated
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James S. Krinsley
cost of $52 500 for 3586 patient days in the interventional group, or approximately $15 per day per patient. Accounting for a conservative rate of inflation of 4% per year, this corresponds with a cost of $24 per day per patient in 2014 US dollars. However, these costs may underestimate the cost of BG monitoring. The 2 primary modes of BG monitoring in current clinical use are blood gas analyzers and bedside glucometers. The cost of BG monitoring using a blood gas analyzer includes the cost of the solute used to perform an individual test (estimated to be $3.78 per test, based on current purchasing cost data from the Stamford Hospital pharmacy) and the cost of the analyzer itself, estimated to be $15 000. Assuming this cost per test, the purchase of 2 blood gas analyzers for the ICU, and a BG testing interval of every 2 hours (which is notably significantly more frequent than was performed by any of the 9 centers in a recently published international observational study6), the cost of monitoring using blood gas analyzers is estimated to be $52.86 per day per patient ($45.36 attributed to the cost of the analyzer cartridges, and $7.50 attributed to the cost of 2 analyzers spread over 4000 patient days). The cost of BG monitoring using glucometers and strips includes the cost of the strips (estimated to be $0.43 per test, based on current purchasing cost data from the Stamford Hospital pharmacy), and the cost of the glucometer, estimated to be $500. Assuming this cost per test, the purchase of 3 glucometers for the ICU, and a BG testing interval of every 2 hours, the cost of monitoring using glucometers and strips is estimated to be $5.54 per day per patient ($5.16 attributed to the cost of the strips and $0.38 attributed to the cost of the 3 glucometers spread over 4000 patient days). In both cases, a liberal estimate of the cost of intravenous tubing and insulin is $50 per day per patient. These estimates do not account for nursing and/or technician time spent performing BG monitoring and treatment, conservatively ranging from 6 to 10 minutes per test for blood gas analyzers and 3 to 5 minutes per test for glucometers.
Sensitivity Analysis: Costs and Savings Attributable to Glycemic Control Assumptions
For the purposes of this sensitivity analysis, 1000 admissions per year to the ICU were assumed, with a mean ICU LOS of 4 days, yielding 4000 patient days per year. Every patient will undergo BG monitoring and treatment every day, with measurement intervals of every 1 hour and every 2 hours entered into the model. The cost differential between an 56
“ICU bed day” and a “floor bed day” is conservatively estimated to be $1000 per day. The attributable cost of an ICU-acquired infection is $25 000. The baseline incidence of ICU-acquired infection is conservatively estimated to be 10% of the patients. An automated spreadsheet is included as a Supplementary File that allows the reader to change the financial assumptions of this analysis to reflect locally derived data.
Costs Table 1 summarizes the cost of glycemic control, including the costs associated with insulin treatment and BG monitoring, based on information received from the pharmacy department at Stamford Hospital. (As an overview of glycemic control practice at Stamford Hospital, the current blood glucose target range for patients admitted to the ICU is 90–120 mg/dL. Monitoring is performed using glucometers [AccuChek Inform 2, Roche Diagnostics, Indianapolis, Indiana] and strips. Blood glucose values 180 mg/dL twice in a row trigger the initiation of IV infusion of insulin and monitoring frequency of q1h. Blood glucose values between 121 and 179 mg/dL are treated with subcutaneous insulin aspart, administered q3h as needed. Insulin dosing is nursedriven. The minimum monitoring frequency for all patients is q3h. Insulin glargine is used to supply a portion of the insulin requirement in some patients whose condition has stabilized and are receiving enteral nutrition. Nutritional support is Table 1. Cost of Insulin Therapy and Glucose Monitoringa Treatment Insulinb Bag of 100 mL NS (for infusion of insulin) Tubing for intravenous infusion Monitoring
$7.20 $1.70 $0.64
Cartridge for blood gas analyzer (cost per test)c q1h q2h q3h Strips for glucometerd
$90.67 $45.36 $30.24
q1h q2h q3h
$10.32 $5.16 $3.44
Current costs obtained from the pharmacy department at Stamford Hospital. Costs are per patient, per day. b Cost of insulin is for continuous regular infusion at 4 U/h for 24 hours ($1.23), or subcutaneous therapy including 30 U/d of insulin aspart and 30 U/d of insulin glargine ($7.20). The higher number is chosen for this estimate. Each insulin concentration is 1 mL = 100 U. Regular insulin (Humulin R): $12.30 per 10-mL vial Insulin aspart: $45.02 per 10-mL vial Insulin glargine: $195.02 per 10-mL vial c Cost of blood gas analyzer cartridge: $1700 for 450 tests = $3.78 per test. d Cost of 50 strips: $21.34 = $0.43 per test. Abbreviation: NS, normal saline. a
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Cost-Effectiveness of Glycemic Control
begun within 24−48 hours in most patients admitted to the ICU, nearly predominantly via the enteral route.) Treatment costs include the cost of the different insulin preparations used and the cost of intravenous tubing and intravenous infusion bags. Two modes of monitoring—blood gas analyzers and glucometers—are compared. In the former case, costs include the purchase of the blood gas analyzers (2 per ICU) and the cost of the cartridge used for analysis. In the latter case, this includes the purchase cost of glucometers (3 per ICU) and the cost of the strips.
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Savings Savings result from reductions in ICU LOS and the occurrence of ICU-acquired infections. Figure 1 illustrates the impact of a 5%, 10%, 15%, and 20% reduction in these parameters, using a range of attributable costs for an ICUacquired infection, in an ICU with a baseline incidence of 10% of patients developing an ICU-acquired infection.
Discussion
This article evaluates available literature to reach conclusions about the beneficial financial impact of implementation of glycemic monitoring and treatment of hyperglycemia in critically ill patients. An important limitation is that only the first Leuven study2 and a large before-and-after study conducted subsequently at Stamford Hospital7 showed
substantial improvements in mortality and morbidity with intensive BG monitoring and treatment of hyperglycemia; data from these 2 investigations also demonstrated substantial cost savings. Other investigations document increased morbidity, particularly ICU-acquired infections and increased ICU LOS, associated with hyperglycemia and hypoglycemia. The substantial cost of nosocomial infections is addressed in other recent work.21,22 Contemporary costs of 2 modalities for BG monitoring, blood gas analyzer and glucometer, are entered into a comprehensive sensitivity analysis to yield an estimate of the net financial impact of glycemic control implementation using a 10% baseline incidence of ICUacquired infection. The cost of glycemic control was estimated assuming every-1-hour and every-2-hour monitoring with glucometers was performed and the cost of strips was $82 780 and $62 140, respectively, for an ICU with 1000 admissions per year, mean ICU LOS of 4 days, and 100% of patient days included. Under the same assumptions, the cost of glycemic control using every-1-hour and every-2-hour monitoring with blood gas analyzers was estimated to be $432 880 and $251 440, respectively. Even with a more conservative estimate of benefit—a 5% reduction in ICU-acquired infection and ICU LOS in an ICU with a very low preimplementation 5% incidence of ICU-acquired infection—glycemic control is associated with a savings of $262 500, yielding a net
Figure 1. Savings and costs associated with glycemic control.
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James S. Krinsley
financial benefit of $11 060 in the model using every-2-hour monitoring with a blood gas analyzer, and $200 360 in the model using every-2-hour monitoring with strips and glucometers. With moderate benefit—a 10% reduction in ICU-acquired infection and ICU LOS—in a unit with 10% preimplementation incidence of HAI, the savings increase substantially to $650 000, yielding strong net financial benefit under each of the scenarios. For an ICU with a 15% preimplementation incidence of HAI that achieves a 15% reduction in ICU-acquired infection and ICU LOS, the savings increase to $1 162 500, representing a substantially higher net financial benefit. Finally, these data were accumulated in the last 10 to 15 years of experience with glycemic control, using currently available technologies. The sensitivity analysis includes monitoring frequencies that are not typically achieved in contemporary clinical practice.6 Increased monitoring frequency will almost certainly improve time in the targeted BG range,23 and offers the promise of improved clinical outcomes for critically ill patients.18
Conclusion
Abnormalities in glucose control, especially hyperglycemia and hypoglycemia, are associated with mortality and substantial morbidity in the critically ill. The financial burden of nosocomial infection and increased ICU and hospital length of stay is considerable. A detailed sensitivity analysis concludes that efforts to ameliorate dysglycemia have a beneficial economic impact.
Conflict of Interest Statement
James S. Krinsley, MD, FCCM, FCCP, discloses a relationship as a consultant and advisory board member with Edwards Life Sciences, OptiScan Biomedical, and Medtronic.
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5. Krinsley JS. Should guidelines for glycemic control of the critically ill be individualized?: weighing the evidence from randomized and observational investigations. Hosp Pract (1995). 2014;42(2):14–22. 6. Krinsley JS, Egi M, Kiss A, et al. Diabetic status and the relationship of the three domains of glycemic control to mortality in critically ill patients: an international multi-center cohort study. Crit Care. 2013;17(2):R37. 7. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic Proc. 2004;79(8):992–1000. 8. van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–461. 9. Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–139. 10. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009;35:1738–1748. 11. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283–1297. 12. Scurlock C, Raikhelkar J, Mechanick JI. The economics of glycemic control in the ICU in the United States. Curr Opin Clin Nutr Metab Care. 2011;14:209–212. 13. van den Berghe G, Wouters P, Kesteloot K, Hilleman DE. Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med. 2006;34(3):612–616. 14. Krinsley JS, Jones RL. Cost analysis of intensive glycemic control in critically ill adult patients. Chest. 2006;129(3):644–650. 15. Sadhu AR, Ang A, Ingram-Drake L, Martinez DS, Hsueh WA, Ettner SL. Economic benefits of intensive insulin therapy in critically ill patients: the targeted insulin therapy to improve hospital outcomes (TRIUMPH) project. Diabetes Care. 2008;31:1556–1561. 16. Yendamuri S, Fulda GJ, Tinkoff GH. Admission hyperglycemia as a prognostic indicator in trauma. J Trauma. 2003;55(1):33–38. 17. Kwon S, Thompson R, Dellinger P, Yanez D, Farrohki E, Flum D. Importance of perioperative glycemic control in general surgery: a report from the Surgical Care and Outcomes Assessment Program. Ann Surg. 2013;257(1):8–14. 18. Okabayashi T, Shima Y, Sumiyoshi T, et al. Intensive versus intermediate glucose control in surgical intensive care unit patients. Diabetes Care. 2014;37(6):1516–1524. 19. Egi M, Bellomo R, Stachowski E, et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc. 2010;85(3):217–224. 20. Krinsley JS, Schultz MJ, Spronk PE, et al. Mild hypoglycemia is strongly associated with increased intensive care unit length of stay. Ann Intensive Care. 2011;1:49. 21. Murphy D, Whiting J. Dispelling the myths: the true cost of healthcareassociated infections. https://www.premierinc.com/safety/topics/ guidelines/downloads/09-hai-whitepaper.pdf. Accessed September 7, 2014. 22. Douglas SR II. The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. Centers for Disease Control and Prevention Web site. http://stacks.cdc.gov/view/cdc/11550. Accessed July 31, 2014. 23. Boyd JC, Bruns DE. Effects of measurement frequency on analytical quality required for glucose measurements in intensive care units: assessments by simulation models. Clin Chem. 2014;60:644–650.
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