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ORIGINAL CONTRIBUTIONS

Received: May 29^th 2013
Accepted: August 11^th 2014

Association of stress hyperglycemia and in-hospital complications

Gerardo Galindo-García,^a María Eugenia Galván-Plata,^b Haiko Nellen-Hummel,^c Eduardo Almeida-Gutiérrez^b

^aServicio de Medicina Interna, Hospital General Regional 2, Villa Coapa

^bCoordinación de Investigación en Salud

^cJefatura del Servicio de Medicina Interna, Hospital de Especialidades, Centro Médico Nacional Siglo XXI

Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Gerardo Galindo-García
Telephone: 55 22 17 98 79
Email: gerardo3g2010@hotmail.com

Background: Stress hyperglycemia is the elevation of serum glucose found in a patient, once he is admitted in the hospital. The objective of this study was to evaluate the impact of admission serum glucose level in the outcome of noncritical hospitalized patients.

Methods: A prospective analytical cohort study was conducted in patients hospitalized in the Internal Medicine service of the Hospital de Especialidades, Centro Médico Nacional Siglo XXI (Instituto Mexicano del Seguro Social), from September 2011 to February 2012.

Results: We included 89 patients with serum glucose level < 110 mg/dL (group A) and 90 patients with serum glucose > 110 mg/dL (group B). Diabetes mellitus was more frequent in group B (p < 0.001). Glycosylated hemoglobin greater than 6.5 % was found in 36.4 % of the patients in group B and in 8.7 % in group A (p < 0.001). Patients in group B had higher APACHE II score (p = 0.02) and worse in-hospital outcomes.

Conclusions: Stress hyperglycemia was associated with higher APACHE II score and more medical complications, such as sepsis, urinary tract infection, pneumonia and use of pressor amines. Mortality independent predictors were systemic arterial hypertension and APACHE II score.

Keywords: Diabetes mellitus; Hyperglycemia; Cross infection.

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Stress hyperglycemia is any elevation of serum glucose at the time of hospital admission in patients with and without previously diagnosed diabetes mellitus.¹

The prevalence of previously undiagnosed diabetes in hospitalized patients varies depending on the population studied. Estimates range from 1.9%, based on the measurement of fasting plasma glucose, to 18% in patients with acute myocardial infarction, based on a test of glucose tolerance, completed three months after discharge in a European study.² Umpierrez et al. studied 2030 patients and found that up to a third of all individuals admitted to a hospital with hyperglycemia had no previous diagnosis of diabetes mellitus.³

Stress hyperglycemia is secondary to increased hepatic gluconeogenesis and peripheral resistance to insulin action due to inhibition of insulin-dependent glucose transporter 4 (GLUT-4), due to the release of counter-regulatory hormones (glucagon, catecholamines), tumor necrosis factor alpha (TNF-α), and interleukin (IL) 1 and 6.⁴ Hyperglycemia per se can induce a proinflammatory state due to cellular glucose overload and cellular oxidative stress from increased free radical production. Moreover, hyperglycemia affects cellular and humoral immunity,⁵ plus being a procoagulant factor.⁶

Several studies have documented the association between hyperglycemia upon admission with the risk of increased mortality and in-hospital complications; in a prospective cohort, Kosiborod et al. studied subjects over 65 years diagnosed with acute myocardial infarction. They showed a linear relationship between hyperglycemia upon admission and mortality at 30 days and one year;⁷ on the other hand, hyperglycemia upon admission is a predictor of mortality and poor functional recovery in non-diabetic patients with ischemic cerebral vascular disease (CVD),⁸ as well as an increased risk of hemorrhagic transformation of ischemic CVD.⁹ It also has been linked to higher rates of postoperative complications in patients undergoing coronary revascularization (CVD, myocardial infarction, sepsis, sternotomy infection, renal failure, need for inotropic drugs, and prolonged mechanical ventilation)¹⁰ and with increased mortality in patients with COPD exacerbation¹¹ and pneumonia secondary to gram-negative bacteria.¹² Stress hyperglycemia is also a marker of disease morbidity and mortality during critical disease.²

In the present study we analyzed the association between stress hyperglycemia and in-hospital complications in the patients of an internal medicine service.

Methods

It was a prospective and analytical study cohort, from September 2011 to March 2012. It included patients of either sex, 18 and up, admitted to the Servicio de Medicina Interna of the Hospital de Especialidades del Centro Médico Nacional (CMN) Siglo XXI. It excluded patients from the Intensive Care Unit (ICU), patients hospitalized for at least 24 hours in another hospital, and patients from other medical or surgical services of the same hospital (transferred service), as well as pregnant women and new mothers.

Decisions regarding the diagnostic and therapeutic approach, ICU admission, and hospital discharge of patients were made by the attending physicians of Internal Medicine. Clinical analyses were performed in the hospital laboratory.

Varying degrees of hyperglycemia on admission were evaluated: Group A (normoglycemia, glucose < 110 mg/dL), Group B (hyperglycemia) with Subgroup B1 (glucose 111-160 mg/dL), Subgroup B2 (glucose 160-210 mg/dL) and Subgroup B3 (glucose > 210 mg/dL). For univariate and multivariate analysis a lower-glucose group was designated at less than 110 mg/dL as the main reference to compare, and this analysis was also conducted among groups with different degrees of hyperglycemia.

Adverse outcomes were defined such as the presence of pneumonia, urinary tract infection, thrombosis (at any level), acute renal disease, gastrointestinal bleeding, cerebrovascular disease, sepsis, need for mechanical ventilatory assistance, surgical wound infection, surgical wound dehiscence, reoperation, ICU admission, and death. The use of antibiotics, vasoactive amines, use of glucocorticoids, and total parenteral nutrition was also recorded.

Descriptive and analytical statistical analysis was done. Quantitative variables are expressed as median (interquartile range), whereas nominal variables are shown with absolute and relative frequencies. The contrast analysis was done using Mann Whitney U test for quantitative variables and with chi-squared or, if necessary, Fisher's exact test for nominal variables; to assess the magnitude of the association between variables, relative risk (RR) was calculated, while multivariate analysis was performed using binary logistic regression, with statistical basis for model input < 0.20 and output  (p ≥ 0.05). SPSS version 20.0 was used (SPSS Inc., Chicago, Illinois, USA).

Results

In this study 179 patients were included; 89 with normoglycemia and 90 with hyperglycemia (Table I). Follow-up was done for all patients during the period of their stay, and there were no losses in the study.

The median age of subjects in the group with stress hyperglycemia was significantly higher compared to the normoglycemic subjects (66 vs 54 years, with an interquartile range of 54-78 for the first and 38-71 for the second, p = 0.003). Diabetes mellitus was more frequent in Group B than in Group A (11.4% vs 48.9%, p < 0.001) as was the presence of hypertension (41.6% vs 62%, p = 0.004). Glycosylated hemoglobin > 6.5% was found in 36.4% of patients in Group B and 8.7% in Group A (p < 0.001). History of ischemic heart disease was significantly higher in Group B (4.5% vs 17.8%, p = 0.004). The other demographic variables and comorbidities were presented similarly in both groups (Table I).

Statin use was more common in the group with hyperglycemia (3.4% vs 13.3%, p = 0.01), and no significant differences were found in the use of other drugs between the two groups (Table II). 

The comparison between the medians of the normoglycemia group versus the stress hyperglycemia group (which was done with Mann-Whitney U) showed that the latter subjects have a significantly higher APACHE II score (8 vs 10 points, respectively, with an interquartile range 4-13 in the first and 6-15 in the second, p = 0.02) and a higher frequency of critically ill patients (defined as APACHE score > 18 points, 14.6% vs 22.2%, p = 0.17). There were similarities in days of hospital stay, where normoglycemic patients had a median of 9 versus 8 in hyperglycemic patients (both groups with an interquartile range of 6-12 and p of 0.40). Also, a clear trend was observed of greater need for the use of amines in the hyperglycemia group (0% vs 4.4%, p = 0.06). Similarly, hyperglycemic patients had a higher rate of nosocomial complications, such as pneumonia, urinary tract infection, acute renal disease, sepsis, and vasopressor drug use, but a statistically significant difference was not demonstrated (Table III).

Upon analyzing comorbidities according to degree of hyperglycemia, a higher percentage of diabetics was found in Subgroup B3 (Subgroup B1, 26%; Subgroup B2, 67%; Subgroup B3, 90%, p < 0.001) as well as glycosylated hemoglobin above 6.5% in Subgroups 2 and 3 (Subgroup 1, 20%; Subgroup 2, 62%; Subgroup 3, 61%; p < 0.001). No other differences were found in demographic characteristics, comorbidities, medication use, or other laboratory values ​​between the three hyperglycemia subgroups.

Study according to hyperglycemia subgroups showed that the percentage of critically ill patients (APACHE II score > 18 points) was higher in Subgroup B3 (Subgroup B1, 19.2%; Subgroup B2, 16.7%; Subgroup B3, 40%, p = 0.09) as was the presence of sepsis, (Subgroup B1, 13.5%; Subgroup B2, 22.2%; Subgroup B3, 20%, p = 0.62), showing no statistically significant difference. Regarding APACHE II measurement, the first two subgroups had a median of 10 and the third had 15, which were compared by Mann-Whitney U (with interquartile ranges 6-14, 7-14, and 10-25, respectively, and a p of 0.10). No differences were found between subgroups in median days of hospital stay (Group B1, 8; Group B2, 6.5; Group B3, 9) or in the presence of in-hospital complications (Table IV).

Finally, multivariate analysis showed an association of mortality with the presence of hypertension (OR 11.79, 95% CI 1.29-107.2, p = 0.02) and for every point that APACHE II rose (OR 1.39, CI 1.16-1.67, p < 0.001), adjusted for age, history of diabetes, glucose upon admission, history of diabetes mellitus, ischemic heart disease, and statin use (Table V).

Discussion

This study shows that stress hyperglycemia is a disorder that occurs frequently in sick subjects who do not have a history of diabetes; only 49% of patients with hyperglycemia were diabetic, and of those 37% had glycosylated hemoglobin above 6.5%, indicating that most of these patients had hyperglycemia as part of the metabolic response to trauma. Of patients with glucose values upon admission ​​above 210 mg/dL (Subgroup 3), up to 43% are critically ill, compared to 15% of patients with normoglycemia. 90% of patients in Subgroup 3 had prior history of diabetes compared with 11% of patients with normal blood glucose (p < 0.001), indicating that patients with previously diagnosed diabetes are more likely to have critical illness. However, Subgroup 1 (glucose between 110-160 mg/dL) also showed a higher percentage of critically ill patients, compared to normoglycemic patients (14.6% versus 22.2%), suggesting that the presence of hyperglycemia, including at such values, confers a poor prognosis; only 26% of these patients had previous diagnosis of diabetes, in addition to which 80% had normal glycosylated hemoglobin.

The presence of in-hospital complications was also higher in the hyperglycemia group, and the frequency of these complications as well as vasopressor amines use increased in tandem with glucose.

No differences were found in the average number of days of hospital stay, ICU admission, death, use of antibiotics and steroids, or percentage of other in-hospital complications.

The results obtained are similar to those of other studies involving patients with various diseases,^8,10-15 which indicates a relationship between stress hyperglycemia on admission and the risk of death and presence of in-hospital complications.

This study has some limitations, including that in some patients it was not possible to measure variables such as serum cortisol and markers of inflammation, which can eventually have an influence, since no biochemical variables influencing clinical outcomes are analyzed; however, the strength of the study is, first, adequate follow-up, and, second, measurement and quantification of clinical variables that give external validity to other populations of second or third level of care. The subgroups with hyperglycemia between 161-220 mg/dL and greater than 210 mg/dL included 18 and 20 patients respectively, which suggests that the sample size per group is not large enough to reject the statistical hypotheses, and which opens a line of research that will need a larger number of patients to determine with sufficient sampling power whether there are significant differences in clinical outcomes between these groups of patients. It is worth mentioning that the Servicio de Medicina Interna of the Centro Médico Nacional Siglo XXI is a focal point for addressing patients with difficult diagnoses, so many have prolonged hospital stays suitable for carrying out the corresponding study protocol, rather than it being due to the severity of the condition itself, so this affects the days of hospital stay of those who were included in this study.
Hyperglycemia associated with stress is a condition that is part of the metabolic response to trauma and it has implications for the prognosis and evolution of hospitalized patients; its recognition and identification will allow the clinician to opportunely treat the condition and to influence the development of the natural history of disease. It is important to note that the measurement of glycated hemoglobin is part of the evaluation of hyperglycemia,¹⁶ and all patients with a value above 6.5% need to initiate a plan of long-term treatment. If intervention is early, it is possible to prevent complications;¹⁷ however, neglecting this prevents adequate control of glucose, in addition to which the patient is exposed to having more hospital complications and a worse prognosis.

Conclusion

Stress hyperglycemia is associated with a trend toward greater in-hospital morbidity in patients of a tertiary care internal medicine service, while history of hypertension and each additional APACHE II point were independent factors associated with mortality.

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