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After completing this continuing education article, the pharmacist should be able to:
1. Identify patients at risk for developing hyperglycemia.
2. Assess the use of intensive intravenous insulin infusions, physiologic subcutaneous insulin therapy, and sliding-scale insulin dosing for hospitalized patients with hyperglycemia.
3. Cite essential elements for successful implementation of a glycemic control program in a hospital or health system.
4. Evaluate insulin delivery systems in inpatient populations.
5. Monitor patients for safety issues after implementing a glycemic control program in a hospital or health system.
6. Discuss the important elements of a care plan when transitioning a patient from one setting to another.
Clinicians, administrators, societies of medicine, leaders in endocrinology, and accrediting agencies are increasingly recognizing the importance of normoglycemia in hospitalized patients. According to recent data, an increased number of patients in the hospital have been diagnosed with diabetes.1 Acute hyperglycemia in hospitalized patients, with or without the diagnosis of diabetes, is a common complication. Up to 40% of hospitalized patients are identified as having hyperglycemia.2 Contributing to this high percentage, even in patients without diabetes, are the many pathophysiologic causes of hyperglycemia in ill patients (Figure).
In hospitalized patients, hyperglycemia results from a combination of endogenous and exogenous sources.3 Underlying beta islet cell failure and peripheral insulin resistance result in increased plasma glucose levels. Additionally, stress hyperglycemia, attributable to increased endogenous levels of counterregulatory hormones (cortisol, glucagon, growth hormone, and epinephrine) and inflammatory mediators (tumor necrosis factoralpha, interleukin [IL]-1, IL-6) (Figure), is commonly seen in acutely ill and postsurgical patients, both with and without diabetes. These mediators promote peripheral and hepatic insulin resistance, increase glycogenolysis, and increase gluconeogenesis fueled by the enhanced peripheral breakdown of substrates. Exogenous sources or causes of glucose from medications, nutrition, and intravenous (IV) fluids further promote already increased blood glucose concentrations (Figure).
Importance of Normoglycemia
Acute hyperglycemia in the hospital setting is closely correlated with increased morbidity and mortality.2,4 Data from the mid-1990s suggest that postoperative hyperglycemia is associated with poor outcomes and increased infection.5-7 Hyperglycemia is a common comorbidity on medical-surgical floors, particularly in patients without the diagnosis of diabetes.8 Similar data in patients who are undergoing cancer chemotherapy or those with stroke, myocardial infarction, kidney transplant, community-acquired pneumonia and critically ill patients demonstrate worse outcomes with poor glycemic control.2,9-19
Although observational studies in non-intensive care unit (ICU) medical-surgical units suggest that normoglycemia may be beneficial, it is not known from these trials whether treating or preventing hyperglycemia will make a difference in outcomes. There are a lack of prospective, randomized, controlled trials examining normoglycemia in non-ICU patients. The majority of the evidence for treating and preventing hyperglycemia comes from the ICU literature.
Van den Berghe and colleagues studied intensive glucose control (target glucose <110 mg/dL) versus conventional glucose control (target glucose <200 mg/dL) in a surgical ICU.20 Intensive treatment demonstrated a significant reduction in mortality, compared with conventional treatment (8.0% vs 4.6%, P = .05). Morbidities that were statistically reduced included sepsis (relative risk [RR] reduction = 46%), need for dialysis (RR = 41%), need for blood transfusions (RR = 50%), and incidence of critical illness polyneuropathy (RR = 44%). A post hoc analysis of patients who stayed in the surgical ICU (SICU) for greater than 5 days demonstrated that patients with average blood glucose values <110 mg/dL had a statistically significant reduction in cumulative inpatient mortality, compared with patients with glucose between 111 and 150 mg/dL (P = .025).21 In a follow-up analysis of these patients, those who stayed in the SICU greater than or equal to 3 days had a statistically significant increase in cumulative 4-year survival (23.1% vs 36.1%, P = .03).22
Van den Berghe and colleagues later tested intensive versus conventional insulin therapy in medical ICU patients.23 The triggers to start insulin and attain glucose goals were the same as in the SICU trial. Intensive treatment resulted in slightly lower mortality (37.3%), compared with the conventional treatment (40.0%); however, this was not significant (P = .33). In patients who remained in the medical ICU greater than or equal to 3 days, a significant decrease in mortality was noted with intensive treatment (43.0% vs 52.5%, P = .009). In the intensive treatment, all patients demonstrated significant reductions in morbidities such as time in the ICU (hazard ratio [HR] 1.15; 96% confidence interval [CI], 1.01-1.53, P = .04), time in hospital (HR, 1.16; 95% CI, 1.00-1.35, P = .05), and time on mechanical ventilation (HR, 1.21; 95% CI, 1.02-1.44, P = .03).
Krinsley and colleagues conducted a "real-world, before-and-after"trial in a mixed medical-surgical ICU.24 A statistically significant reduction in mortality (P = .002) was observed after the intensive insulin program was implemented. This trial suggests that the benefits of intensive insulin can be reproduced outside of the research setting.
These studies suggest that implementing glucose control measures can improve morbidity and mortality in hospitalized patients.
Inpatient Target Glucose Goals
There seems to be a clear association between hyperglycemia and poor outcomes; however, the exact glucose target that would provide maximum improvement in outcomes remains unknown. Although the landmark Van den Berghe studies show promise, further studies are needed to identify the ideal targets. The current recommendations from the American Diabetes Association (ADA) and the American College of Endocrinology (ACE) regarding target glucose levels for hospitalized patients are shown in Table 1.25,26 It is widely believed that certain subsets of patients will benefit from different targets. Patients with glycemic emergencies and/or other acute metabolic derangements, such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state, will require additional metabolic therapy and different glycemic targets than the ones outlined in Table 1.
Glycemic Control in the Hospital: Cultural and Systems-based Changes
Achieving glycemic control in hospitalized patients will require evolution of medical culture within the institution. Hospitals must adapt to the growing body of evidence supporting glucose control in all hospitalized patients.3,27 Explanations for the lack of awareness and failure to implement initiatives include unknown generalizability of results of published clinical trials, lack of a comprehensive how-to guideline, insufficient knowledge of recommended treatment options, entrenched practice patterns, high turnover rate of physicians, familiarity with the challenges of achieving consensus glucose control standards, and desire for more confirmatory evidence.3,28 Endorsement of hospital glucose control initiatives by authoritative bodies at the professional and institutional level can aid in providing guidance, education, and benchmarking opportunities needed to change hospital culture both locally and nationally.29,30
"Physical champions"serve as the driving force for implementing glycemic control interventions.3 Physical champtions can be a single or small group of clinicians willing to devote the time, conduct the research, and gather the resources needed to guide and implement a change in practice.3 Physical champions consist of physicians, nurses, pharmacists, and nutritionists who are willing to undertake the long and tedious process of changing glucose control practice in their institution.3 The physical champion organizes the cascade of events needed to implement hospital glucose control interventions and guidelines that promote efficacy and safety.3 A stepwise approach to developing, implementing, and maintaining hospital-wide glucose control interventions is outlined in Table 2.
Physical champions are largely involved in the formation of multidisciplinary committees consisting of hospitalists, intensivists, nurses, pharmacists, endocrinologists, diabetologists, nutritionists, administrators, and information systems personnel responsible for patient care and different institutional resources. Incorporating a multidisciplinary approach will ensure input, commitment, and continuous feedback to help promote dissemination and compliance with glucose control initiatives throughout the institution.3 The committee must have the authority to coordinate quality improvement initiatives involving glycemic control throughout the institution.3 This group can also help with the creation of "local champions."These local champions can be pharmacists in many patient care areas of the institution implementing and maintaining interventions set forth by the multidisciplinary committee.
Optimizing glucose control in the institutional setting requires integration of clinical, administrative, laboratory, and technological resources. Clinicians must work within the limits of their institution to use available systems resources to implement glycemic control interventions.3 Examples of common glycemic control interventions requiring systems interventions include dissemination of guidelines/algorithms/policies; medication order entry templates (subcutaneous [SC] insulin, oral hypoglycemics, and IV insulin protocols); electronic medication administration records; automated dispensing systems; nutrition order entry templates; and nutrition delivery. Efficacy and safety data synthesized from electronic resources allow for rapid and continuous assessment of glycemic control interventions throughout the institution.31
IV Insulin Protocols
Although the ideal goal for glucose in the ICU is as close to 110 mg/dL (normal) as possible,25 no ideal IV protocol is available that can be easily adopted to achieve this goal. Many IV insulin protocols are readily available in the literature; however, few have been rigorously evaluated, and even fewer are designed to reach a tight glucose goal of 80 to 110 mg/dL. When adopting or creating an IV insulin protocol at individual institutions, many variables need to be assessed.
"Ideal"IV Insulin Protocol
Throughout the multidisciplinary, stepwise approach as outlined above, the pharmacist may be involved at many levels of decision making, including selecting the type of IV insulin protocol to be instituted at their hospital. The ideal IV insulin protocol should be easy to order, easy to use, easy to implement, effective, and safe and have preset automatic reminders for blood glucose checks and insulin initiation. A protocol that never stops the insulin infusion until an order to do so provides the advantage of making the protocol appropriate for all patients, including those with type 1 diabetes who require insulin at all times to avoid DKA. Because IV insulin is not ideal for covering elevations in glucose related to meals beyond clear liquids, the ideal protocol should have provisions for providing prandial doses of SC insulin for those patients who may be eating meals while on IV insulin. Finally, the protocol should take into account the patient's insulin sensitivity by the use of a multiplier protocol. This can be accomplished by prescribing insulin adjustments based on a multiplication factor that considers the previous glucose value, the current glucose value, and the current rate of insulin infusion.
Two basic multiplier protocol formats include (1) paper and (2) electronic. The electronic protocol may reduce error by eliminating the need for calculations. Electronic protocols include an automatic prompt for glucose draws/insulin adjustment on a predetermined schedule. Another advantage of an electronic multiplier protocol is the ability to change patient-specific glucose goals. At this point, the use of electronic protocols is limited by the expense of the hardware and software and compatibility with an institution's computer hardware and software.
Paper multiplier protocols do not have information system compatibility issues, potentially making the implementation faster, easier, and less expensive than the electronic multiplier protocol. They may lend themselves to poor compliance, through calculation errors, as well as a lack of an automatic reminder to check glucose.
Developing/Adopting a Protocol
As discussed earlier, in order for an IV insulin protocol to be successfully implemented, institutional buy-in and support through the Pharmacy and Therapeutics Committee, ICU leadership, and hospital administration is vital. All stakeholders should agree upon the goal glucose concentrations for specific patient populations throughout the institution. These goals will be one of the primary markers of quality as the project moves forward.
An approach to increase the likelihood of the protocol being ordered in a timely fashion is to use an opt-out approach. Opt-out orders imply that all patients in the unit have a standing order to start the IV insulin protocol when certain conditions are met (eg, the patient has type 1 diabetes or a glucose value over a prespecified number). The decision to opt out or discontinue the IV insulin order can be made at the discretion of the ordering clinician.
While implementing programs to improve glucose control, continuous quality assessment is vital. Postimplementation quality assessments can be used to determine if an institution is reaching its glucose target.3 If quality assessment measures reveal areas for growth, adjustments through further quality improvement strategies may be necessary and repeated until the target is achieved.
Inpatient SC Regimen
Most hospitalized patients exhibiting hyperglycemia will require 3 insulin components to effectively attain ADA and ACE glycemic goals while minimizing the risk of hypoglycemia (defined as glucose values <50 mg/dL).2,25,26 These components include basal, nutritional (prandial), and correctional (supplemental) coverage.
Basal insulin controls glucose during fasting and between meal states. This is typically provided through intermediate-acting insulin (eg, neutral protamine Hagedorn [NPH]) and long-acting insulin analogs (eg, glargine, detemir). Nutritional and correctional insulin provide coverage for hyperglycemia secondary to intake of calories via meals, tube feeds, dextrose solutions, or total parenteral nutrition (TPN). This is typically provided through short-acting insulin (eg, regular insulin) or rapid-acting insulin analogs (eg, lispro, aspart, glulisine). Correctional insulin is given concomitantly with the scheduled nutritional dose to cover unexpected hyperglycemia, which occurs despite the use of scheduled basal and nutritional insulin. Correctional insulin is a useful tool for insulin "dose-finding"and titration strategies.2 The amount of correctional insulin used in a day helps to determine subsequent daily dosage adjustments.
Schnipper and colleagues conducted a prospective cohort study of 107 adult patients with diabetes or inpatient hyperglycemia to determine insulin-prescribing patterns on a general-medicine service.32 They found that basal insulin was ordered for only 43% of patients, while nutritional dosing of rapid-or short-acting insulin was ordered for only 4% of patients. The remaining patients were either treated with sliding scale only or received no insulin therapy at all. For busy practitioners, the creation of an appropriate inpatient SC insulin regimen may be difficult, resulting in many patients receiving only sliding-scale insulin. Sliding-scale insulin provides correctional insulin coverage when glucose values reach a prespecified value. Sliding-scale monotherapy does not incorporate basal or nutritional insulin. Although this strategy has been widely considered to be ineffective for more than a decade when used on its own, it appears to have prevailed for multiple reasons.33,34 Clinicians may not be aware of literature suggesting superior strategies of glucose management, or they may not know how to implement recommended insulin regimens. Limitations of sliding-scale monotherapy include difficulty tailoring to individual patient requirements, presence of hyperglycemia before insulin is administered, and increased risk of hypoglycemia.25,26 Both the ADA and ACE recommend against the use of sliding-scale insulin as monotherapy.25,26
When initiating SC insulin therapy in the inpatient setting, it is important to consider several factors?the patient's prior home regimen (if any) and level of glucose control (if applicable), nutritional status, clinical status, and concomitant medications (Table 3). Although not all patients requiring treatment for hyperglycemia in the hospital have diabetes, those patients with an established outpatient diagnosis may be medically managed in the outpatient setting with oral hypoglycemic agents, insulin, incretin mimetics, amylinomimetics, or an approved combination of these agents. Because hospitalizations are frequently unstable situations, the efficacy of oral hypoglycemics may be limited by changes in overall clinical status, renal and hepatic function, nutritional intake, or contrast administration. Inability to rapidly titrate oral agents puts patients at risk for both hyper-and hypoglycemia. In most cases, oral hypoglycemics should be discontinued upon hospital admission.
Initial Dose Selection
In the outpatient setting, patients are treated with a wide array of SC insulin regimens (basal only, basal-nutritional, nutritional only). It is recommended that all patients with diabetes have an A1C reading obtained within about a month of admission to the hospital.34 This will help determine a patient's level of glucose control in the outpatient setting and assist in discharge planning. In general, patients who are well-controlled can be continued on their home dose, unless there is a major change in nutritional or clinical status.
A daily insulin dose for patients not receiving insulin at home or for those with hospital-(or stress-) induced hyperglycemia may be estimated by a weight-based formula. For most patients, a conservative estimate for a total daily dose (TDD) is 0.3 to 0.7 units/kg/day.2,25,35 Patients who are very insulin-resistant may require doses as high as 0.4 to 1.0 units/kg/day2,35 or even greater. One way to approach the regimen is to administer about 50% of the TDD as basal (usually given as intermediate-or long-acting) insulin and the other 50% divided throughout the day as nutritional (usually provided as rapid-or short-acting) insulin (see Case). This is intended as a starting point only, as hospitalized patients often require high insulin doses to attain target glucose levels.2
Patients who are eating discreet meals should receive rapid-acting insulin (aspart, lispro, or glulisine) 0 to 15 minutes prior to the first bite. The dose may be the same as the patient's home dose or calculated by the above calculation or prior insulin requirements. Some institutions may utilize advanced carbohydrate counting, which tailors the insulin dose to each meal. For patients receiving continuous nutrition via enteral tube feeds or caloric intake via dextrose infusion, short-acting insulin (regular insulin) is preferred, given every 4 to 6 hours. Lower doses may be necessary for patients who are not at goal caloric intake. If tube feeds are bolused or cycled, regular insulin can be administered while tube feeds are running. For patients on TPN, one approach is to determine a TDD using IV insulin for 24 hours. The following day, one half (nutritional component) of the TDD can be added to the TPN mixture, while the remaining (basal) needs are provided with scheduled intermediate-or long-acting insulin. Correctional insulin should be administered every 4 to 6 hours.
Nutritional insulin should be held if a patient is not eating or if an interruption in nutritional intake takes place. The use of rapid-or short-acting insulin for nutritional coverage will reduce the risk of hypoglycemia caused by an interruption in nutritional intake. When patients are receiving nutritional insulin as well as basal insulin via intermediate-or long-acting insulin, the risk of hypoglycemia is increased when nutrition is interrupted.
Correctional (supplemental) insulin is the third component of the optimal SC insulin regimen. Dosing should be based on total daily insulin requirements and administered in addition to the nutritional dose (Table 436). Correctional insulin is beneficial to control elevations in glucose prior to nutritional excursions as well as to assist subsequent dose adjustments. The daily insulin regimen should be updated based on the previous 24-hour glucose values and correctional insulin usage.
Adjustments to insulin regimens in response to clinical considerations (marked hyper-or hypoglycemia, renal function, steroid doses, obesity, or severity of underlying illness) are required for all hospitalized patients. Fluctuation in nutritional status and caloric intake can have a profound impact on an SC regimen. While in the hospital, patients may eat full meals, eat less than at home, be on NPO (nothing by mouth) status, or receive tube feeds, TPN, or continuous dextrose infusion. The amount and method of caloric intake influences the nutritional (prandial) insulin requirements and may change on a daily (or meal-to-meal) basis. Variations in clinical status also acutely affect glucose values and corresponding insulin requirements. Critically ill patients who are not controlled on an SC regimen, are receiving vasopressor agents, or have potential for erratic SC absorption can be converted to IV insulin therapy.
Barriers to Glucose Control in Hospitalized Patients
Despite the availability of published evidence and guidelines to aid in the management of hospital glucose control, attaining established goals of therapy remains difficult. Health care providers face many potential barriers to providing optimal glycemic control to the different patient populations throughout their institution.3 Fear of hypoglycemia remains one of the top barriers to normoglycemia. Table 5 highlights the major barriers to achieving glucose control in hospitalized patients. Identifying and developing strategies to overcome these barriers is essential to ensure glycemic control and improve patient outcomes.3
Transition from IV to SC Insulin Regimen
Unfortunately, no standardized approach exists for transitioning to SC insulin in the literature. Multiple approaches can be taken, but the general principles of these approaches are very similar.37,38
The first step to transitioning to an SC insulin regimen is to determine the TDD of SC insulin to use. This is estimated by taking the rate of insulin infusion for the past 6 to 8 hours and extrapolating this to determine the 24-hour requirements.
Once the TDD of insulin is determined, the dose is divided into a basal and nutritional SC insulin regimen. At this point, it is important to know the patient's nutritional status when determining the TDD and the nutritional status moving forward. If the patient was not receiving any nutrition (D5W [dextrose 5% in water], TPN, tube feeds), the majority of the TDD of insulin is basal. If the patient is going to continue to be NPO, then nutritional insulin will not be necessary. For patients eating meals or on tube feeding, the TDD of insulin could be roughly 50% basal and 50% nutritional.
One approach for transitioning from a continuous IV insulin infusion to SC insulin was recently tested in a randomized controlled fashion.37 In this study, the TDD of insulin was determined by calculating the average rate of IV insulin infusion from the previous 6 hours and multiplying by 4. Patients were randomized to receive 40%, 60%, or 80% of this amount as insulin glargine given at the time of the conversion. Prandial insulin aspart was added to the SC regimen when the patient was tolerating oral intake, and dosage was left to clinical judgment. With this approach, blood glucose values within the range of 80 to 150 mg/dL in the 24 hours following the conversion were 58.7%, 44.4%, and 67.6% in the 40%, 60%, and 80% groups, respectively (overall, P = .001). The incidence of hypoglycemia was <1% in all groups.
Generally, the first dose of the SC basal insulin should be given at least 2 hours prior to discontinuing IV insulin. Importantly, the insulin regimen used when transitioning to SC from IV insulin is probably not going to be perfect on day 1. Therefore, doses of insulin need to be addressed at least daily, as described previously in the SC insulin section.
Recent recommendations from the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) have highlighted the need for institutions to critically evaluate their methods of insulin delivery. In December 2005, the American Society of Health-System Pharmacists published practice guidelines for the safe use of insulin in the inpatient setting, detailing recommendations supported by current literature, JCAHO, and the Institute for Safe Medication Practices.39 This document recommends that all scheduled doses of intermediate-and long-acting insulin be prepared by the pharmacy to be used immediately or be available as patient-specific delivery devices. The position statement also recommends removal of all floor-stock, multiple-use insulin, with the exception of regular insulin, which is only to be available for specified clinical indications.
Patient-specific insulin delivery devices are a relatively new method for reducing insulin errors in the inpatient setting. Insulin delivery devices provide a more accurate dose measurement and can be utilized with a safety needle. In a recent analysis of managed care claims data, a switch from vial and syringe to an insulin-pen device resulted in improved clinical and economic outcomes.40 In the outpatient setting, patients who converted to insulin-pen therapy displayed greater adherence to insulin therapy and a reduction in hypoglycemic events. Additionally, a significant decrease in hypoglycemia-associated emergency department visits and physician visits was observed.
Thorough attention to the discharge plan is of utmost importance to enhance understanding and compliance. Additionally, a hospital stay provides an important opportunity for the health care provider to promote diabetes care, especially for those patients who are not well controlled in the outpatient setting. The discharge plan should be tailored to each patient's needs.
Most patients should be discharged on a regimen similar to the home regimen prescribed by their primary care physician. Reassessment of the regimen should occur when the patient has a new contraindication to an admission medication, has evidence of severe hyperglycemia (eg, very high A1C), or presents with hypoglycemia on the admission regimen. If a patient who was not on insulin prior to admission requires insulin at the time of discharge, the discharge insulin regimen should usually be as simple as possible (eg, a single injection of bedtime NPH, glargine, or detemir). An exception for this is the newly diagnosed type 1 diabetes patient, who should be discharged with a home regimen of 3 to 4 injections per day. Patients generally should not be discharged to home on sliding-scale insulin. Patients who require insulin injections after discharge should receive instruction on how to inject the insulin. If a medication has been changed or added, patients should have prompt follow- up with their primary care physician.
Patients newly diagnosed with diabetes should be discharged on a simple regimen and provided close follow-up with a dedicated provider who will closely follow their progress. For patients with no history of diabetes but who are found to have hyperglycemia during hospital admission, studies show that approximately 60% of this population will meet diagnostic criteria for diabetes at followup testing.41 Arrangements should be made for these patients to have followup testing for diabetes (eg, fasting plasma glucose) within 1 to 2 months following hospital discharge.
Ideally, the outpatient regimen should be finalized at least 24 hours prior to actual discharge.35 This will help to identify and target any immediate problems that may occur. After discharge, close follow- up is important, since changes in diet, physical activity, and medications are likely to alter the regimen.
Diabetes Self-management Education
Teaching diabetes self-management to patients in hospitals is a challenging task. Since patients are hospitalized because they are ill, they are in an environment that is not conducive to learning. Ideally, people with diabetes should be taught at a time and place conducive to learning, such as an outpatient setting in a recognized program. For the hospitalized patient, diabetes "survival skills"education is generally considered most appropriate. Patients are taught sufficient information to enable them to go home safely. Survival skills include information regarding nutrition and exercise, self-monitoring of blood glucose, medication administration, how to avoid hypoglycemia and hyperglycemia, sick-day guidelines, and planning for postdischarge self-management support.
Hyperglycemia in hospitalized patients is a common occurrence and is associated with increased morbidity and mortality. Institutions seeking to implement the recommendations of authoritative bodies face many challenges at the clinical and administrative levels. Strategies to achieve normoglycemia include adoption or creation of IV and SC insulin protocols, incorporation of electronic resources, standardization of insulin delivery, and transition of care. Consideration of these factors is needed to improve the efficacy and safety of glucose control at the institution and to improve patient outcomes.
Paul M. Szumita, PharmD, BCPS, Clinical Pharmacy Practice Manager, Department of Pharmacy, Brigham and Women's Hospital, Boston, Mass; Bonnie Greenwood, PharmD, BCPS, Senior Pharmacist, Department of Pharmacy, Brigham and Women's Hospital, Boston, Mass; Kevin Anger, PharmD, BCPS, Senior Pharmacist, Department of Pharmacy, Brigham and Women's Hospital, Boston, Mass; Merri Pendergrass, MD, PhD, Director of Clinical Diabetes, Department of Medicine, Brigham and Women's Hospital, Boston, Mass
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41. Levetan CS, Passaro M, Jablonski K, Kass M, Ratner RE. Unrecognized diabetes among hospitalized patients. Diabetes Care. 1998;21:246-249.