Review Article
The clinical impact of inpatient hypoglycemia

https://doi.org/10.1016/j.jdiacomp.2014.03.002Get rights and content

Abstract

Hypoglycemia is common in hospitalized patients and is associated with poor outcomes, including increased mortality. Older individuals and those with comorbidities are more likely to suffer the adverse consequences of inpatient hypoglycemia. Observational studies have shown that spontaneous inpatient hypoglycemia is a greater risk factor for death than iatrogenic hypoglycemia, suggesting that hypoglycemia acts as a marker for more severe illness, and may not directly cause death. Initial randomized controlled trials of intensive insulin therapy in intensive care units demonstrated improvements in mortality with tight glycemic control, despite high rates of hypoglycemia. However, follow-up studies have not confirmed these initial findings, and the largest NICE-SUGAR study showed an increase in mortality in the tight control group. Despite these recent findings, a causal link between hypoglycemia and mortality has not been clearly established. Nonetheless, there is potential for harm from inpatient hypoglycemia, so evidence-based strategies to treat hyperglycemia, while preventing hypoglycemia should be instituted, in accordance with current practice guidelines.

Introduction

Hospitalized patients with and without diabetes have frequent dysglycemia, and both hyperglycemia and hypoglycemia are associated with poor outcomes. Inpatient hyperglycemia is associated with increased mortality and in-hospital complications (Umpierrez et al., 2002). However, while initial small studies of aggressive glycemic control with intensive insulin therapy (IIT) showed improved clinical outcomes (Van den Berghe et al., 2006, van den Berghe et al., 2001), subsequent large-scale trials reported high rates of hypoglycemia and even suggested harmful effects of intensive glucose lowering (Brunkhorst et al., 2008, NICE-SUGAR Study Investigators, 2009, Preiser et al., 2009). It is now clear that patients with both spontaneous and iatrogenic hypoglycemia are also at particularly high risk of complications, including longer and more expensive hospital stays and increased mortality rates (Boucai et al., 2011, Garg et al., 2013, Turchin et al., 2009). Hospitalized patients who are elderly or severely ill are especially vulnerable to the adverse effects of inpatient hypoglycemia (Boucai et al., 2011). In addition, most inpatient studies of IIT have been conducted in the intensive care unit setting, with very little evidence to guide optimal treatment of patients admitted to the general medical wards. Therefore, in this review we stress the importance of safely avoiding dysglycemia in hospitalized patients, and offer strategies to prevent hypoglycemia. We also highlight the distinction between iatrogenic and spontaneous hypoglycemia, and present evidence that hypoglycemia is a marker of more severe illness, rather than a direct cause of poor outcomes.

Section snippets

Definition of hypoglycemia

The definition of hypoglycemia has been a topic of debate, since the range of “normal” glucose levels and the threshold for symptoms vary between individuals. In the outpatient setting, true hypoglycemia is often defined as the threshold at which counterregulation occurs. In relatively healthy outpatient populations, counterregulatory hormonal responses, with release of epinephrine and glucagon, can begin to occur when blood glucose levels fall below ~ 70 mg/dL. With progressive hypoglycemia

Incidence of inpatient hypoglycemia

Among patients with and without diabetes admitted to general medical wards, the incidence of hypoglycemia (defined as blood glucose levels  70 mg/dL) ranges from 3.5% to 10.5% (Boucai et al., 2011, Cook et al., 2009). In patients with diabetes, hypoglycemia can occur in 12%–18%, with even higher rates reported when more aggressive antihyperglycemic therapy is used (Wexler, Meigs, Cagliero, Nathan, & Grant, 2007). For example, hypoglycemia defined as a point-of-care glucose  70 mg/dL was reported in

Risk factors for hypoglycemia

Multiple factors contribute to the development of hypoglycemia in hospitalized patients. Although diabetes and use of glucose lowering medications are the most common risk factors, only about one half of hypoglycemic events occur in patients with diabetes or receiving insulin treatment (Boucai et al., 2011, Kagansky et al., 2003, Krinsley and Grover, 2007). Spontaneous hypoglycemia, which occurs without a clear precipitant, must be distinguished from drug-induced or iatrogenic hypoglycemia,

Acute consequences of hypoglycemia

Hypoglycemia can cause acute inflammatory, cardiovascular and neurologic changes. In experimental models, hypoglycemia causes an increase in catecholamine levels and inflammatory markers, platelet activation and endothelial dysfunction (Gogitidze Joy et al., 2010, Schwartz et al., 1987, Wright et al., 2010). Hypoglycemia in healthy controls and subjects with T1DM causes an increase in platelet monocyte adhesion and markers of platelet activation (P-selectin) and inflammation (monocyte CD-40,

Mortality associated with hypoglycemia

As noted above, both hypoglycemia and hyperglycemia in hospitalized patients are associated with increased mortality, length of stay and complications (Turchin et al., 2009, Umpierrez et al., 2012). In large, observational studies a J-shaped curve exists between blood glucose level and the risk of mortality, with the lowest mortality risk falling between blood glucose levels of ~ 5.6 and 8.7 mmol/l (100–156 mg/dL) (Bagshaw, Egi, George, & Bellomo, 2009). In patients with acute coronary syndrome a

Randomized trials of intensive insulin in hospitalized patients

The association between optimal inpatient glucose levels and improved outcomes has been repeatedly demonstrated. However, trials attempting to target near-normoglycemia in hospitalized patients have had mixed outcomes. The concept of providing insulin therapy during acute illness is not new: Glucose, Insulin and Potassium (GIK) were routinely recommended since the mid-1950s in patients with myocardial infarction in order to decrease myocardial irritability during ischemia (Fath-Ordoubadi &

Prevention of hypoglycemia

Based on cumulative results of clinical trials and observational data, consensus guidelines now recommend targeting a fasting or pre-meal blood glucose < 140 mg/dL, and a random blood glucose < 180 mg/dL in non-critically ill hospital inpatients (Table 2) (Moghissi et al., 2009a, Umpierrez et al., 2012). The Endocrine Society guidelines also recommend that in patients who are able to maintain glycemic control without hypoglycemia, “a lower target range may be reasonable” (Umpierrez et al., 2012).

Glucose monitoring

Handheld point-of-care (POC) meters have greatly facilitated the ability to monitor blood glucose and respond rapidly to suspected hypoglycemia. However important limitations must be considered in the hospital setting (Hellman, 2012). These monitors need proper maintenance and calibration, as well as specialized training for users. The FDA requires that results from POC meters used in the hospital remain within 20% of laboratory blood glucose values 95% of the time. Thus a 5% rate of inaccuracy

Conclusion

Hypoglycemia remains a common problem in hospitalized patients with and without diabetes, and is associated with excess mortality. Hypoglycemia correlates with severe illness, which may explain the association between hypoglycemia and death, particularly since multiple large studies have failed to conclusively demonstrate that hypoglycemia directly causes mortality. Although clinicians can be somewhat reassured that the risk of mortality from iatrogenic hypoglycemia is low, it is nonetheless

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    Disclosures: This article was partially supported by National Institutes of Health P60 Grant DK20541, which supports the Diabetes Research and Training Center of Albert Einstein College of Medicine. E. Brutsaert and M. Carey have no conflicts of interest to report. J. Zonszein serves as a speaker and consultant for the following companies: Novo Nordisk, Takeda Pharmaceuticals North America, Merck/Schering-Plough Pharmaceuticals, Janssen Pharmaceutical, Sanofi-Aventis, Eli Lilly, Boehringer Ingelheim.

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