Abstract/ PDF

The association between blood glucose levels and hospital outcomes in patients admitted with acute exacerbations of chronic obstructive pulmonary disease

Nagham Jafar MDa, Hawa Edriss MDb, Ebtesam Islam MD PhDc, Kenneth Nugent MDd

Correspondence to Nagham Jafar MD. 
Email: drnaghamsaeed@yahoo.com

+ Author Affiliation - Author Affiliation
a a reserch assistant in the Department of Internal Medicine at TTUHSC.
b a resident in Internal Medicine at TTUHSC in Lubbock, TX.
c a fellow in pulmonary and critical care medicine in Internal Medicine.
d a pulmonary physician in the Department of Internal Medicine.

SWRCCC 2014;2(7)1:-11  
doi:10.12746/swrccc2014.0207.082

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Abstract

Patients with acute exacerbations of chronic obstructive pulmonary disease usually require an escalation in medical management and often require hospitalization. The outcomes from these episodes depend on the severity of the underlying chronic lung disease, the degree of acute respiratory failure superimposed on the chronic lung disease, comorbidity, and possibly hospital related complications. Hyperglycemia represents an independent risk factor for hospital associated complications and/or mortality in other medical diagnoses, such as stroke and acute myocardial infarction. Recent studies in patients with acute exacerbations of COPD demonstrate that hyperglycemia is associated with an increased length of hospital stay, failure of noninvasive ventilation, and/or mortality. Acute stress and medications used with an acute flare, such as glucocorticoids and beta agonists, increase blood glucose levels. The explanation for poor outcomes likely involves an increase in colonization with pathogenic bacteria, acute changes in host defenses, and possibly metabolic disorders related to hyperglycemia and glycosuria. Patients with acute stress and glucocorticoid related hyperglycemia often have higher blood glucose levels in the afternoon and early evening. Consequently, this problem may be overlooked if clinicians depend on routine a.m. laboratory tests. Therefore, patients with acute flares in COPD should have bedside point of care glucose measurements during the early course of their hospitalizations. Patients with high glucose levels require nutritional management and/or insulin treatment. We need more prospective studies to determine the degree of hyperglycemia in these patients, the acute consequences, and the best management strategies.

Keywords: COPD exacerbation, hyperglycemia, length of stay, mortality and morbidity

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Introduction

Patients with chronic obstructive pulmonary disease (COPD) have acute exacerbations approximately 1.3 times per year. These exacerbations range in severity from transient decreases in functional status to fatal events. In the United States, exacerbations have contributed to a 102 percent increase in COPD-related mortality from 1970 to 2002 (21.4 to 43.3 deaths per 100,000 persons).1 Effective management of an acute exacerbation of COPD (AECOPD) requires symptom relief and reducing the risk for subsequent exacerbations. Identification of patients at risk for more complicated hospital courses should facilitate in-patient management, and risk factors for adverse outcomes include lower arterial pHs, older age, male gender, underlying comorbidities, disease severity, and in-hospital complications.2 Hyperglycemia is associated with poor outcomes in patients with pneumonia,3 myocardial infarction,4 and stroke,5 but the effect of hyperglycemia on outcomes during AECOPD has not been definitely established. Recent Global Initiative of Chronic Obstructive Lung Disease (GOLD) and American Thoracic Society guidelines do not comment on the control of blood glucose during COPD flares.


The effect of hyperglycemia on outcomes of acute COPD exacerbation

Hyperglycemia is very common in any acute illness, and its pathophysiology includes acute increases in peripheral insulin resistance and hepatic glucose production caused by increases in glucocorticoids, catecholamines, and pro-inflammatory cytokines.6 Below we summarize studies that have evaluated the effect of hyperglycemia in patients admitted with AECOPD (Table).

Baker, et al. concluded that hyperglycemia (blood glucose >126 mg/dl) is associated with an increased risk of death and prolonged hospital stays (more than nine days) independent of age, sex, and a previous diagnosis of diabetes.7 This study also showed that in the subgroup of patients who had COPD confirmed by spirometric testing, the blood glucose quartile independently predicted adverse clinical outcomes, but the underlying COPD severity did not. This was a retrospective case control study conducted by retrieving data from electronic medical records for 284 patients admitted with AECOPD to St. George’s Hospital (UK) between 2001 and 2002. In this study, only the highest blood glucose recorded for the patients during their hospital stay was used for analysis, and patients were grouped according to their blood glucose quartile (group 1, <108 mg/dl, n = 69; group 2, 108–125 mg/dl, n = 69; group 3, 126–160 mg/dl, n = 75; and group 4, >160 mg/dl, n = 71).The relative risk (RR) of death or a longer inpatient stay was significantly increased in group 3 (RR 1.46, 95% CI 1.05 to 2.02, p = 0.02) and group 4 (RR 1.97, 95% CI 1.33 to 2.92, p<0.0001) compared to group 1. For each 18 mg/dl increase in blood glucose the absolute risk of an adverse outcome increased by 15% (95% CI 4%to 27%, p = 0.006). Also hyperglycemia was associated with colonization of sputum with multiple pathogens and with Staphylococcus aureus in this study.

The relationship between hyperglycemia and non-invasive ventilation (NIV) outcomes in COPD patients was investigated in a prospective study by Chakrabarti, et al..8 These authors concluded that hyperglycemia on admission is associated with NIV failures. Eighty-eight COPD patients presented with acute type II respiratory failure and had NIV initiated within 24 hours of admission. Random blood glucose levels were measured before NIV use. Hyperglycemia was present at baseline in 50% of patients; 16 (18%) had a pre-existing diagnosis of diabetes mellitus. NIV failure occurred in 34% of patients (15/44). It was significantly more common in patients with hyperglycemia (34%) than in patients without hyperglycemia (2%). Blood glucose levels were higher in patients with NIV failure (162.7 ±58 mg/dl vs. 127±39.2 mg/dl; p=0.003). It is not known whether hyperglycemia is a direct cause of poor outcomes in AECOPD or whether it is a marker for other adverse factors, such as coexisting comorbidities, treatment strategies, or the severity of illness. This study provided some insight into the possible underlying mechanisms since the NIV failure in AECOPD was independent from oral corticosteroid use immediately before admission, underlying diabetes mellitus, pH and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores.

Moretti and colleagues studied 186 patients admitted to a respiratory intensive care unit with respiratory failure characterized by a mean pH of 7.23± 0.07 and a mean PaCO2 of 85.3 ±15.8 mm Hg9. The study used logistical regression analysis to analyze factors associated with noninvasive respiratory failure after an initial success (late failures). The presence of metabolic complications (found in >20% of the late failures) predicted late failures (more than 48 hrs) of NIV after an initial success. The most frequent metabolic complication was hyperglycemia (defined as blood glucose >200 mg/dl) which was present in all the patients with metabolic disorders. However, all hyperglycemic patients who developed late failure to NIV also developed pulmonary infection during the course of their hospital stays, and this likely contributed to NIV failure or death.

Burt, et al. reported that length of hospital stay is increased by 10% (21hours) for each 18 mg/dl increase in mean glucose (P=0.01).10 In this study the blood glucose levels of 47 patients were monitored continuously using a device to measure interstitial glucose levels to determine the pattern of hyperglycemia in patients receiving prednisolone for AECOPD. Higher mean daily glucose levels were positively associated with longer hospital stays; this relationship with length of stay was not significant for other markers of disease severity. Parappil et al. retrospectively analyzed 172 patients admitted with AECOPD, including 39 patients with comorbid diabetes mellitus.11 In this study the presence of DM was associated with increased length of stay (mean 7.8 days) and mortality (8%) in comparison with patients without DM (6.5 days and 4% mortality), but these differences were not statistically significant.

Kasirye, et al. studied 209 hospitalized patients with AECOPD to evaluate factors associated with in-hospital complications, length of hospitalization, 30-day hospital readmission, and 90-day all-cause mortality. The study analysis failed to reveal any associations between higher blood glucose levels and adverse outcomes but did find that low glucose levels (less than 90 mg/dl) were associated with increased hospital complications and increased length of stay in these patients.12 This study had three important differences when compared to the Baker study. 1) It used WHO/GOLD criteria and previous spirometric measurements to define population with AECOPD, while the Baker study used only ICD-10 codes. 2) This study used radiological information to rule out other comorbidities, like pneumonia, which might confer a confounding effect on the data. 3) This study used daily mean blood glucoses to identify hyperglycemia, since blood glucose levels among AECOPD patients on systemic corticosteroids tend to peak in the afternoon and evening hours. Therefore, blood glucose measurements taken throughout the day more accurately reflect a patient’s glycemic status. Other studies have utilized either single admission blood glucose or a single peak blood glucose obtained fasting or non-fasting during hospitalization.

Hypoglycemia is not a usual finding in AECOPD, because hyperglycemia often develops secondary to stress hormones release, cytokines,13 and treatment with systemic corticosteroids.14 The presence of hypoglycemia may be a marker for severity of illness if its presence is not related to a treatment side effect. It could reflect defects in glucose counter-regulation. Therefore, the patient’s inability to develop a hyperglycemic response might portend adverse clinical outcomes.15,16

Studies demonstrating that hyperglycemia is associated with poor outcomes in AECOPD usually do not identify the possible pathophysiology. In one cross sectional observation study, the glucose levels of intubated patients were measured in bronchial secretions and blood, and the sputum was cultured for pathogenic bacteria.17 This study demonstrated that glucose was detected in airway secretions in patients with hyperglycemia and the risk of colonization with MRSA was markedly increased in the presence of glucose (relative risk 2.1; 95% CI 1.2 to 3.8). In addition, the presence of MRSA was associated with infiltrates on the chest radiograph, increased levels of C reactive protein, and prolonged ICU stays (approximately seven days).17 The Baker study also showed that hyperglycemia was associated with a significant increase in the presence of multiple pathogens and MRSA in the sputum.18 Hyperglycemia may increase the rate of colonization, and these changes in flora in association with abnormal host defenses increase the risk of infection and adverse outcomes.


AECOPD management and glucose metabolism

Hyperglycemia (defined as blood glucose level more than 200 mg/dl ) in acutely ill patients with no prior diagnosis of diabetes, including those admitted for AECOPD, has been linked to several factors, including medications and stress responses to acute illness. It has been reported that more than 38% of patients admitted to the hospital have hyperglycemia (defined by in-hospital fasting glucose level of ≥126 mg/dl or a random blood glucose level of 200 mg/dl).19 COPD itself may be considered as a novel risk factor for new onset type 2 diabetes mellitus through multiple pathophysiological alterations, such as inflammation, oxidative stress, insulin resistance, weight gain, and alterations in metabolism of adipokines.20,21,22 Moreover, infection (a potential cause of AECOPD) can lead to hyperglycemia by the development of peripheral insulin resistance and alterations in hepatic glucose metabolism, leading to the overproduction of glucose and failure of the liver to appropriately adapt when nutritional support is administered.23 We will discuss briefly the factors that can affect glucose metabolism in AECOPD patients.


Neuroendocrine and inflammatory stress responses

In acute illness, glucose production is increased, peripheral glucose utilization is decreased, and this leads to increased plasma glucose levels. This response appears to be mediated by a combination of neurohumoral changes, lipid mediators, and cytokine production. Increased serum concentrations of glucagon, adrenaline, and cortisol occur in response to a variety of pathophysiological stresses. As a part of the acute stress response, reversible insulin resistance develops, and peripheral glucose uptake decreases.24 Stress in acutely ill patients can also lead to increased catecholamine secretion, which can contribute to hyperglycemia.25


Hypoxia

Oltmanns, et al. studied 14 healthy male volunteers. These men were subjected to 30 minutes of hypoxia (O2 saturation =75%) and normoxia (O2 saturation= 96%) under conditions of a euglycemic clamp.26 This study concluded that acute hypoxia causes glucose intolerance. Hypoxia also increased plasma epinephrine levels, heart rates, and anxiety. Several animal studies have shown the development of insulin resistance after periods of intermittent hypoxia.27,28 Louis and Punjabi studied the effect of intermittent induced hypoxia on 13 healthy volunteers using an intravenous glucose tolerance test to assess insulin dependent and independent glucose disposal. The study showed that intermittent hypoxia caused insulin resistance and defective insulin independent glucose disposal.29 Pallayova, et al. concluded that intermittent hypoxia is associated with damage to pancreatic beta cells.30 Animal studies have also demonstrated that both acute and chronic sustained hypoxia can cause insulin insensitivity and hyperglycemia.31


Acidosis

AECOPD can be complicated by hypercapneic respiratory failure and respiratory acidosis. Studies have shown that respiratory acidosis causes glucose intolerance by inducing hepatic and peripheral insulin resistance.32 In addition, animal studies suggest that metabolic acidosis can cause impaired insulin secretion.33


Medications

a.  Glucocorticoids: Hyperglycemia is a well-recognized complication of corticosteroid therapy. At the University of Pittsburgh, a retrospective study concluded that hyperglycemia occurs in the majority of hospitalized patients receiving high doses of corticosteroids (≥40 mg per day).34 Since poor outcomes are associated with hyperglycemia, these authors suggested that a protocol should be followed to measure glucose levels in all patients receiving high dose corticosteroid therapy. Glucocorticoids cause hyperglycemia by inducing insulin resistance, increasing liver gluconeogenesis, and impairing pancreatic β-cell function.35,36

b.  Beta agonist medications and other catecholamines: Several animal and human studies have demonstrated that B2-agonists can affect glucose levels by altering pancreatic insulin secretion, liver metabolism, and glucose uptake.37 The overall result is hyperglycemia, which can be clinically significant in patients with AECOPD, since many of these patients take corticosteroids, have sedentary lifestyles, and are overweight. Studies have shown that catecholamines lead to hyperglycemia directly by affecting the pancreas, by increasing glucagon secretion, or by exerting a direct effect independent of pancreatic hormone release.38,39

c.  Antibiotics: Several antibiotics have been reported to cause abnormalities in glucose metabolism and can cause both hyperglycemia and hypoglycemia. Fluoroquinolones are the only antibiotics consistently associated with hyperglycemia.40 A large cohort with 78, 433 diabetic patients were followed over a 23 month period to determine the relative risk of hyperglycemia and hypoglycemia in association with antibiotic treatment. The absolute risk for hyperglycemia was 1.6 per 1000 persons for macrolides, 2.1 for cephalosporins, 6.9 for moxifloxacin, 3.9 for levofloxacin, and 4.0 for ciprofloxacin. The adjusted odds ratios for fluoroquinolones compared to macrolides were 2.48 for moxifloxacin, 1.75 for levofloxacin, and 1.87 for ciprofloxacin.41 Yamada, et al. showed that chronic treatment with gatifloxacin decreases islet insulin content by inhibiting insulin biosynthesis.42 Park Wyllie, et al. studied 470 patients treated for hyperglycemia within 30 days after antibiotic therapy and found that gatifloxacin was associated with an increased risk of hyperglycemia (adjusted odds ratio, 16.7; 95 % confidence interval, 10.4 to 26.8).43

d.  Theophylline: In an animal study, aminophylline administration caused hyperglycemia possibly by the induction of insulin resistance.44 Another study with preterm infants showed that plasma glucose levels increased after theophylline therapy was started in infants with respiratory problems.45


Effect of hyperglycemia on inflammatory cell responses, the immune system, and tissue injury

Diabetes mellitus, hyperglycemia, and impaired glucose tolerance are associated with increased C-reactive protein, interleukin-6, and tumor necrosis factor-α.46 Yorek, et al. studied the pro-inflammatory effect of glucose in vitro and showed that incubation of endothelial cells in high glucose concentrations results in radical oxygen species production and activation of the transcription factor nuclear factor-kappa B and an increase in monocyte adhesion.47 Glucose levels have regulatory effects on some pro-inflammatory cytokines.48 Interestingly, these cytokines (IL-6, IL-18, and TNF-α) have been implicated in the development of insulin resistance, atherosclerotic plaque rupture, and future cardiovascular events, and this could explain the association between hyperglycemia and cardiovascular events.49

Several studies have concluded that hyperglycemia can alter cellular defense mechanisms during infection. High glucose levels alter the immune system by decreasing neutrophil degranulation during inflammation, by causing defects in adherence,50 and by impairing phagocytosis,51 chemotaxis,52 bacterial killing, and the respiratory burst.53 Hyperglycemia can also reduce protease secretion by neutrophils, leading to decreases in antimicrobial activity.54 Turina, et al concluded that short term hyperglycemia affects all major components of innate immunity and impairs the ability of the host to control infection.55 Von Kanel reported that a short term rise in blood glucose levels in normal individuals can lead to a decrease in the number of lymphocytes and cause redistribution in lymphocytes subsets.56 These abnormalities are reversed when glucose is lowered.57 A recent review suggested an association between diabetes and a decreased risk of lung injury, possibly mediated by reduced inflammatory responses secondary to hyperglycemia.58


Management of hyperglycemia during acute COPD exacerbations

Hyperglycemia is a common problem in hospitalized patients and can be both a difficult and costly problem during patient care. Observational and randomized controlled studies suggest that good glycemic control in hospitalized patients improves outcomes in both medical and surgical patients. The Endocrine Society, the American Diabetes Association, the American Heart Association, the American Association of Diabetes Educators, the European Society of Endocrinology, and the Society of Hospital Medicine conducted a group meeting to formulate evidence-based practice guidelines for the management of hyperglycemia in hospitalized patients in the non-critical care setting. The following is a brief summary of their recommendations.59

1.  Diagnosis of hyperglycemia and diabetes mellitus in hospitalized patients:

2.  Monitoring blood glucose levels: Use point of care blood capillary testing with accurate devices, and time the glucose readings according to the patient’s nutritional intake and medication schedules.

3.  Glucose level targets: Aim for a premeal glucose level less than 140 mg/dl and random levels less than 180 mg/dl. However, these numbers should be adjusted according to the patient`s clinical situation. For example, allow glucose levels up to 200 mg/dl for terminally ill patients or patients with a high risk for hypoglycemia. To avoid hypoglycemia, patients with glucose values below 100 mg/dl should have their antidiabetic regimens modified.

4.  Management of hyperglycemia: Nutritional therapy should be included as a component of the glycemic management program, and patients shall receive a consistent amount of carbohydrates with each meal. Oral hypoglycemic agents should be stopped, and insulin therapy should be started as the preferred method to achieve good glycemic control.

5.  Special situations:
6.  Hypoglycemia: Prompt recognition and treatment are crucial.

7.  Glycemic control program: Start in the hospital.

8.  Education: Patient and professional education on diabetes management and avoidance of hypoglycemia.

The management of blood glucose levels in critical care settings is a controversial topic with several randomized controlled trials comparing “tight” to “loose” blood glucose control. The large international randomized controlled trial (“the NICE-SUGAR Study”) demonstrated target blood glucose of less than 180 mg/dl resulted in lower mortality than a target of 81 to 108 mg/dl in critical care units.60


Discussion

In this review, we have discussed studies that suggest a relationship between hyperglycemia and poor outcomes in AECOPD. However, these studies do not completely explain the pathophysiology underlying these complications. Also, one study failed to find a relationship between hyperglycemia in patients with AECOPD and reported that hypoglycemia was associated with poor outcomes. Other studies have reported poor outcomes in patients with diabetes mellitus and hyperglycemia who are admitted for different medical conditions, such as myocardial infarction61 and cerebrovascular accidents.62,63 Krinsley studied the relationship between hyperglycemia and hospital mortality in a heterogeneous group of critically ill patients and concluded that even modest hyperglycemia after intensive care unit admission was associated with a substantial increase in hospital mortality in patients with a wide range of medical and surgical diagnoses.64 Animal model studies and other observational studies suggest that possible mechanisms include defective immune responses and an increased risk of infection, increased thrombotic events, increased oxidative stress, and increased inflammatory markers.65 Several studies have shown that hyperglycemia is associated with increased numbers of pathogens and MRSA colonization of the sputum.


Conclusion

Hyperglycemia has been associated with increased morbidity, increased mortality, and longer lengths of stay, and more hospital costs in patients with both medical and surgical conditions. AECOPD is associated with hyperglycemia due to the stress related hormonal response to acute illness and possibly some of the medications routinely used in the treatment of AECOPD. Several studies suggest that hyperglycemia has adverse outcomes in patients with AECOPD, but the pathophysiology underlying these effects has not been determined. We need more research on outcomes in AECOPD in patients with hyperglycemia, using larger sample sizes and taking into consideration a design which can control for cofounders and provide more insight into the pathophysiology. In addition, a study on targeted glycemic control and outcomes is needed.


Key points

  1. Clinical studies have shown that hyperglycemia is associated with adverse outcomes in hospitalized patients in general medical and surgical wards and in critical care units.
  2. Studies have associated hyperglycemia in AECOPD with increased morbidity, mortality, and length of stay.
  3. The pathogenesis underlying these adverse outcomes may include decreases in the immune responses to infection, increased susceptibility to infection, and increased tissue injury.
  4. The timing and number of glucose measurements used to characterize the hyperglycemia in these studies have been variable. More consistent glucose measurements, including late afternoon and early evening, might identify associations better.
  5. A single study found a correlation between hypoglycemia and poor outcomes. This result might suggest that hypoglycemia indicates a failure of the normal body response to stress which leads to adverse outcomes.
  6. The management of hyperglycemia associated with hospitalization requires both detection and treatment. Insulin is the preferred drug for treatment.

Table Summery of the studies investigating the relationship between blood glucose level and COPD exacerbation outcomes

table

AECOPD-acute exacerbation of chronic obstructive pulmonary disease; DM-diabetes mellitus; NIV-noninvasive ventilation; CGMS-continuous glucose monitoring system

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Received: 05/04/2014
Accepted: 06/30/2014
Reviewers: Joaquin Lado, MD
Published electronically: 07/15/2014
Conflict of Interest Disclosures: none

 

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