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Received: May 14^th 2014

Accepted: October 6^th 2014

Management of hyperglycemia in hospitalized patients

Abraham Edgar Gracia-Ramos,^a María del Pilar Cruz-Dominguez,^b Eduardo Osiris Madrigal-Santillan,^c José Antonio Morales-González,^d Olga Lidia Vera-Lastra^e

^aDepartamento de Medicina Interna. Hospital de Especialidades “Dr. Antonio Fraga Mouret”, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México.

^bDivisión de Investigación en Salud. Hospital de Especialidades “Dr. Antonio Fraga Mouret”, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México.

^cLaboratorio de Medicina de Conservación. Escuela Superior de Medicina, Instituto Politécnico Nacional, Distrito Federal, México.

^dLaboratorio de Medicina de Conservación. Escuela Superior de Medicina, Instituto Politécnico Nacional, Distrito Federal, México.

^eMedicina Interna. Hospital de Especialidades “Dr. Antonio Fraga Mouret”, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México.

Communication with: Abraham Edgar Gracia-Ramos

Telephone: 01 (55) 5724 5900, extension 23214

Email:ken_monsters@hotmail.com

Diabetes is a global health problem and Mexico rank sixth in prevalence of this entity. In our country, is the leading cause of death and is a major cause of hospital care being responsible for about 1 in 5 discharges. In the hospital setting, it has been observed that hyperglycemia, both diabetic and non-diabetic patients, is associated with an increased risk of complications, disability and death, and that adequate control in the blood glucose level produces a reduction in these complications. With these bases, several associations have recommended the treatment of hospital hyperglycemia through insulin administration, with the therapeutic goal of maintaining a fasting blood glucose level between 100 – 140 mg/dL and glucose at any time of day less than 180 mg/dL. The insulin application method most recommended consisting in a basal-bolus regimen which has shown efficacy with a low risk of hypoglycemia. The usual practice of the application of insulin through a correction scheme should be abandoned because it is inefficient and involves risks.

Keywords: Diabetes mellitus; Hyperglycemia; Hospitalization; Insulin

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Diabetes mellitus (DM) comprises a group of frequent metabolic disorders that share the common phenotype of hyperglycemia.¹ Type 2 diabetes mellitus (DM2) represents between 85 and 95% of all cases of this disease, which represents a serious public health problem worldwide.

According to the International Diabetes Federation, approximately 382 million people worldwide suffer from this disease, which represents 8.3% of the adult population, and it is estimated that this figure will increase to 592 million by 2035. Mexico ranks 6th in DM2 prevalence.² According to ENSANUT 2012, the number of people previously diagnosed with DM in our country is 6.4 million, representing 9.2% of the population over 20 years old, with the highest prevalence reported in the group between 50-69 years old.^3,4 Based on national mortality statistics, diabetes is the leading cause of death in both men and women since 2000, and the mortality rate increases by 3% each year.^5,6 In 2009, DM was responsible for 77,699 deaths, accounting for 13.76% of all deaths.⁷ As for the demand for hospital services, diabetes is among the main reasons for seeking second and third level care.⁸ In the United States, approximately one in four patients admitted to hospitals have diagnosed diabetes, and about 30% of patients with diabetes require 2 or more hospitalizations per year.^9,10 In Mexico, the Instituto Nacional de Ciencias Médicas “Salvador Zubirán” of the Secretaría de Salud, reported that diabetes was responsible for 26% of discharges, while doctors at Hospital General "Manuel Gea Gonzalez" of the Secretaría de Salud, and Hospital "Adolfo Lopez Mateos" of the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), identified it as responsible for 33 and 20% of discharges, respectively.⁸ In the population covered by the Instituto Mexicano del Seguro Social (IMSS), the prevalence of diabetes in 2010 was 10.5%, ranking eighth as the reason for hospital discharges.¹¹ Historically, hyperglycemia in hospitalized patients had been considered little more than an epiphenomenon of the disease.¹² However, it has now been identified as a risk factor for hospital complications, disability, and death, and it has also been seen that adequate control of it can improve clinical outcomes.^9,13-15

Impact of hyperglycemia in hospitalized patients

Patients with diabetes are 2-5 times more likely to be hospitalized than those without diabetes, and many of these patients are not diagnosed before hospitalization.¹⁶ Observational studies in the United States report that hyperglycemia is present in 32 to 38% of hospitalized patients who are not in an intensive care unit (ICU), and about a third of those have no previous diagnosis of diabetes.^9,17 In Mexico, according to a retrospective study in an IMSS regional hospital, 69% of diabetic patients had hyperglycemia at the time of hospitalization.¹⁸ Hyperglycemia, in both diabetic and non-diabetic patients, is associated with adverse outcomes. In a retrospective study of 1886 patients admitted to a community hospital, hyperglycemia was observed in 38% of cases, of which a third had no previous diagnosis of diabetes, which was associated with increased mortality and hospital stay, as well as a higher number of admissions to an intensive care unit and greater disability after discharge.⁹ A multicenter prospective cohort study involving 2471 patients with community-acquired pneumonia revealed that glucose concentration over 198 mg/dL at admission was associated with higher mortality (13% versus 9%, p = 0.03) and complications (29% versus 22%, p = 0.01) compared with patients with a lower glucose concentration.¹⁹ In another retrospective study of 384 patients with chronic obstructive pulmonary disease and respiratory infection, the relative risk of death increased by 2.1 times when fasting serum glucose was between 126 and 160 mg/dL, and by 3.42 times when it was greater than 160 mg/dL compared to the risk of those with less than 110 mg/dL.²⁰ Observational studies suggest that high glucose levels, especially in non-diabetics, are associated with increased morbidity, mortality, and less functional recovery in patients who have suffered a cerebrovascular event.^21,22 Likewise, in patients suffering from acute coronary syndrome, hyperglycemia- in both diabetics and non-diabetics- has been associated with increased morbidity and mortality.^23,24

Surgical patients who develop hyperglycemia also show an increased risk of adverse outcomes. In a case-control study, high concentrations of glucose increased the risk of postoperative mortality in non-cardiac and non-vascular elective surgery. Patients with preoperative random glucose concentration of between 110-200 mg/dL or above 200 mg/dL, had between 1.7 and 2.1 times respectively higher mortality compared with those with glucose levels less than 110 mg/dL.²⁵ Another study examined the relationship between perioperative glucose control and the rate of postoperative infections in 100 diabetic patients undergoing elective surgery. It was found that the infection rate increased by 2.7 times in those patients who reached serum glucose greater than 200 mg/dL in the first postoperative day. In addition, it was found that those with glucose higher than 200 mg/dL had 5.7 times greater risk of getting a severe infection.²⁶

Pathophysiology

In the hospital setting, many factors are involved in the development of hyperglycemia. Mechanisms of this disorder vary depending on the patient’s glucose tolerance and insulin production ability, as well as the type, severity, and stage of disease, in addition to the drugs used for its treatment27 (Figure 1). Hyperglycemia is often the manifestation of a critical illness, the result of an acute metabolic and hormonal change associated with response to injury and stress.28 The release of counter-regulatory hormones (such as catecholamines, cortisol, growth hormone, and glucagon) results in several abnormalities in carbohydrate metabolism, including insulin resistance, increased hepatic glucose production, impaired peripheral glucose utilization, and relative insulin deficiency.^27,28 Hyperglycemia induces the transcription of proinflammatory factors, such as nuclear factor κβ (nuclear factor κβ, NFκβ) and binding protein-1 activator. The increase of these transcription factors is associated with increased expression of genes encoding various proteins that can mediate inflammation, platelet aggregation, apoptosis, and endothelial dysfunction.^27,28

Hyperglycemia is also associated with an increase in the generation of reactive oxygen species. The increase in observed oxidative load with hyperglycemia is associated with damage to lipids, proteins, and DNA. Superoxide production and its reaction with nitric oxide (NO) under these conditions results in the peroxynitrite production, protein nitration, and NFκβ activation if euglycemia is not reestablished.^25,26

Diagnostic and therapeutic goal

Hospital hyperglycemia is defined as any glucose value greater than 140 mg/dL.^29,30 Patients with hyperglycemia can be classified in one of the following categories:^27,31 a) having previous diagnosis of diabetes; b) without previous diagnosis of diabetes but who are carriers of the disease, and c) having hyperglycemia due to stress, not carriers of diabetes, and whose hyperglycemia is transient.

To distinguish between these two groups a measurement of glycated hemoglobin (HbA1c) can be made, in which a value above 6.5% suggests the presence of undiagnosed diabetes.³⁰

According to the American Diabetes Association (ADA), the Endocrine Society, the American Heart Association (AHA), the American Association of Diabetes Educators (AADE), the European Society of Endocrinology, and the Society of Hospital Medicine, the goals of glycemic control for a hospitalized patient in a non-critical area should be fasting glucose of less than 140 mg/dL, and glucose at any time of day less than 180 mg/dL.^29,30 These treatment goals have been obtained from expert opinion, by extrapolating the results of studies in medical and surgical critically ill patients, and by analyzing retrospective studies that have associated hyperglycemia with adverse results.^32,33

Treatment

Prospective randomized trials in critically ill patients have shown that strict glucose control with insulin reduces short and long-term mortality, the incidence of multiple organ failure, systemic infections, length of stay in an intensive care unit, and total hospital costs.^13-15 Also, in patients with DM2 hospitalized in a general surgical ward, it has been shown that insulin therapy reduces the frequency of complications, such as surgical wound infections, bacteremia, pneumonia, and renal or respiratory failure.³⁴ Based on these results, the use of insulin to control glucose levels in patients hospitalized outside an intensive care unit is recommended.^29,30 The use of antidiabetic drugs is not recommended because it is associated with the occurrence of adverse effects that may result in complications.35 Sulfonylureas are long-acting secretagogues that can cause severe and prolonged hypoglycemia, particularly in the elderly,  and patients with renal disease or poor diet. Short-acting insulin secretagogues (such as repaglinide and nateglinide) have a risk of hypoglycemia similar to sulfonylureas. Metformin should be avoided in patients with decompensated congestive heart failure, renal failure, hypoperfusion, or chronic lung disease, and in patients with risk of developing renal failure and lactic acidosis. Thiazolidinediones require several weeks to reach their full hypoglycemic effect, limiting their use in the hospital, besides being contraindicated in patients with congestive heart failure, hemodynamic instability, or with evidence of hepatic dysfunction.^16,29,35 Regarding the use of inhibitors of dipeptidyl peptidase IV and peptide analogs similar to glucagon-1 (glucagon-like peptide-1, GLP-1) it has been suggested that they may have a role in treating patients hospitalized for low risk of hypoglycemia, although well-conducted clinical trials are needed to demonstrate their safety and efficacy.^36,37

The recommended regime of insulin administration is a basal-bolus treatment that includes a preparation of intermediate or long-acting insulin as basal insulin (to suppress hepatic release of glucose during fasting and between meals), a human or analogous fast-acting formulation of prandial insulin (to prevent postprandial glucose peaks) and a correction scheme also with regular or fast-acting insulin (supplemental dose to lower glucose that is above control ranges).^29-31 There are various schemes employing this administration regime in different ways and that have been implemented in hospitals, but few have proven effective in clinical trials.^{12,16,31,33-35,38-40} Table I shows examples of the basal-bolus regimen in accordance with the recommendations of the Endocrine Society Clinical Practice Guideline.29  Once treatment begins, the doses of basal insulin and prandial boluses should be adjusted based on the total dose of insulin correction administered in the past 24 hours. When insulin correction is required before most meals, it is often necessary to increase the dose of basal insulin. When blood glucose remains consistently high at a specified time, one should adjust the dose of prandial insulin prior to measurement.29 One way to make the adjustment of the insulin dose is also shown in Table I.

The regular administration of insulin with a scale to correct hyperglycemia, which is still widely used, is not recommended since it has been proven ineffective to control glucose, in addition to being associated with an increased risk of hypoglycemia and hyperglycemia.29 The studies RABBIT 2 and RABBIT 2-Surgery demonstrated that a basal-bolus regimen with glargine-glulisine insulin was more effective in achieving glucose levels less than 140 mg/dL than administration of regular insulin with a scale in both medical and surgical patients respectively.^34,38

As for the effectiveness of human insulin in the treatment of these patients, the DEAN study showed that use of a regimen with NPH (neutral protamine Hagedorn) insulin plus regular insulin was as effective as a scheme with detemir and aspart insulin for glycemic control, and there was no difference in the frequency of hypoglycemia.³⁹

Despite this, the implementation of the basal-bolus regimen is low, probably because of its complexity and the fear of hypoglycemia, which led to the study Basal Plus, where it was shown that a scheme with glargine insulin as basal plus additional correction doses of glulisine insulin is as effective as the basal-bolus regimen with the same insulins, so this system can be an alternative treatment scheme.⁴⁰

Transition to outpatient care

Planning the treatment that the patient is to continue when they leave the hospital is a crucial management step that can help reduce visits to the emergency room and re-hospitalization.²⁹ This should take into account various factors such as the time of diagnosis of diabetes, HbA1c level, associated comorbidities, education on disease care, and family and financial support.^31,35 Table II shows an example of this management plan.³¹

Conclusions

Hyperglycemia occurs frequently in both diabetic and nondiabetic hospitalized patients, and its presence is associated with an increased risk of complications, disability, and death. However, several studies conducted in intensive care units have demonstrated that controlling glucose levels leads to a reduction of these complications. On this basis, treatment of these patients through insulin administration is recommended in order to maintain a fasting glucose level between 100-140 mg/dL and glucose at any time of day less than 180 mg/dL. The recommended dosing regimen consists of basal insulin, prandial insulin, and correction scheme. Such treatment would replace the usual insulin monotherapy with correction scheme, as this is inefficient and even bears some risks.

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