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(Chest. 2004;126:879-887.)
© 2004 American College of Chest Physicians

Relationship of Baseline Glucose Homeostasis to Hyperglycemia During Medical Critical Illness*

Cynthia M. Cely, MD; Pratheep Arora, MD; Andrew A. Quartin, MD, MPH; Daniel H. Kett, MD and Roland M. H. Schein, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Drs. Cely, Quartin, Kett, and Schein), University of Miami, Miami, FL; and the Division of Nephrology (Dr. Arora), Columbia University and Harlem Hospital Center, New York, NY.

Correspondence to: Andrew Quartin, MD, MPH, Section of Critical Care Medicine (111), Miami VAMC, 1201 NW Sixteenth St, Miami, FL 33125; e-mail: aquartin{at}med.miami.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objective: To elucidate the relationship of baseline glucose control and acute stimuli with hyperglycemia during medical critical illness.

Design: Prospective cohort study.

Setting: Medical ICU (MICU) of a university affiliated hospital.

Patients: Convenience sample of 100 medical patients meeting criteria for severity of illness and anticipated length of stay and not admitted to the hospital for diabetic ketoacidosis or a hyperglycemic hyperosmolar state.

Interventions: None.

Measurements and main results: Patients were categorized as having normal, abnormal, or unevaluable baseline glucose control based on history and glycosylated hemoglobin (HbA1c). Data collection included blood glucose measurements within 120 h of MICU admission, and dosing of norepinephrine, corticosteroids, propofol, and carbohydrates. Average blood glucose and times over glycemic thresholds were calculated using linear interpolation. Hyperglycemia (glucose > 110 mg/dL) was pervasive in all groups. Among the 51 patients with normal baseline glucose control, HbA1c was correlated with hyperglycemic time (p < 0.01, R2 = 0.15). Multiple regression found HbA1c, age, corticosteroid dose, and carbohydrate administration independently associated with hyperglycemic time (p < 0.05 for each, total R2 = 0.49) in these patients, while body mass index, APACHE (acute physiology and chronic health evaluation) II, norepinephrine dose, propofol dose, gender, and sepsis were not associated with time > 110 mg/dL. Among normal subjects, HbA1c was independently predictive of peak and average glucose, and the fraction of time glucose was > 150 mg/dL and > 200 mg/dL (p < 0.05 for each). Patients with abnormal baseline glucose control had significantly more hyperglycemia than patients with normal baseline control.

Conclusions: Even in patients without evidence of abnormal glucose homeostasis at baseline, hyperglycemia is common during critical illness. Time exposure to hyperglycemia is correlated with acute stressors and baseline glucose regulation, as characterized by HbA1c. Patients with low HbA1c levels are less disposed to hyperglycemia during severe illness than patients with higher, but still normal, HbA1c.

Key Words: blood glucose • critical care • critical illness • diabetes mellitus • glycosylated hemoglobin A • hyperglycemia


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Hyperglycemia occurs frequently among critically ill patients, including those with trauma,12 acute stroke,34 myocardial infarction,56 and sepsis.7 The definition of hyperglycemia during critical illness has varied widely, with most investigators choosing values well above the upper limit of normal.89101112131415161718192021222324 A more stringent definition, designating blood glucose values > 110 mg/dL as hyperglycemic,25 was employed for a recent trial of insulin therapy in a surgical ICU (SICU). Virtually all patients in that trial, most of whom were admitted following cardiac surgery, acquired hyperglycemia during their ICU stay. Aggressive maintenance of euglycemia was associated with reduced morbidity and mortality. The investigators24 argue that glucose levels previously considered unremarkable are pathologic, at least in SICU patients.

The impact of baseline glucose regulation on the severity and duration of hyperglycemia during acute severe illness has not been well studied. Measurements of the predominant glycosylated fraction of hemoglobin A (HbA1c) are widely employed for evaluating averaged glucose levels over a 2- to 3-month period,26272829 and provide a method for assessing baseline glucose control in acutely hyperglycemic patients. Several investigations143031 have examined the relationship between hyperglycemia and HbA1c in patients with acute myocardial infarction, but not the influence of baseline homeostasis on hyperglycemia during other severe medical illnesses.

Glucose normalization may eventually prove beneficial in severely ill nonsurgical patients. It is important to characterize glycemic regulation in this group, both in terms of glucose levels and time exposure to modest but potentially harmful hyperglycemia. We investigated patterns of glycemia in a population of nonoperative medical ICU (MICU) patients, focusing on the relative contributions to hyperglycemic time of acute conditions and baseline glucose regulation.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Study Population
A convenience sample (determined only by investigator availability for the period of study) of patients admitted to the MICU of Jackson Memorial Hospital, a tertiary hospital affiliated with the University of Miami, was studied prospectively. The MICU treats patients with a variety of conditions, including sepsis, respiratory failure, circulatory insufficiency, renal dysfunction, GI hemorrhage, and complications of AIDS. The Institutional Review Board approved the enrollment of 100 patients in this study and waived the requirement for informed consent, provided that all laboratory studies done for study purposes be performed on samples remaining from clinical testing.

Screening was carried out within 24 h of MICU admission by two of the investigators (C.M.C. and P.A.). Patients were eligible for enrollment if they had not been previously treated in an ICU during the current hospitalization (including at transferring hospitals), were expected to require intensive care for > 48 h, and were anticipated to have an APACHE (acute physiology and chronic health evaluation) II score32 > 11. Patients with diabetic ketoacidosis, hyperglycemic hyperosmolar states, and hemoglobinopathies were excluded, as were those who had major surgery prior to MICU admission.

Data Collection
Demographic data, including age, sex, ethnicity, and insurance status were collected. Diabetes mellitus history and corticosteroid exposure in the 24 h preceding MICU admission were recorded. Physiology and laboratory data were collected for calculation of the APACHE II score. Body mass index (BMI) at MICU admission was calculated. Survival was followed through hospital discharge. Diagnoses and conditions apparent within 24 h of MICU admission were selected from a prespecified list, based on the clinical judgment of the investigators. Patients with sepsis, ARDS, disseminated intravascular coagulation, lymphoma, vasculitis, or connective tissue disorders were further classified as having an inflammatory process.

All blood glucose measurements made during the first 120 h of the MICU stay were recorded, as was each dose of insulin. Bedside glucose measurements were made with a plasma-calibrated glucometer (OneTouch SureStep; LifeScan; Milpitas, CA), and laboratory and bedside glucose measurements were considered equivalently. Records were also kept of dextrose infusions (including parenteral nutrition and medication diluents), norepinephrine, propofol, systemic corticosteroids, and enteral carbohydrates administered during this interval.

HbA1c was measured (Variant II; Bio-Rad Laboratories; Hercules, CA) if residual blood was available from a clinical specimen within 120 h of MICU admission. The laboratory range of normal at Jackson Memorial Hospital for HbA1c is 4.7 to 6.4%. The number of units of RBCs transfused within the week preceding HbA1c determination was recorded. If a sample was available, HbA1c was measured again several days after the first specimen, and the number of units of RBCs transfused between HbA1c specimens was recorded.

Patient Classification
Patients were classified as having normal, abnormal, or indeterminate baseline glucose control based on initial HbA1c values and diabetes history. HbA1c results were considered invalid in patients who had received ≥ 2 U of RBC transfusion prior to the tested blood sample being drawn, and these patients were classified as having indeterminate baseline control. Patients who never had residual blood available for HbA1c analysis were also classified as having indeterminate baseline glucose control.

Patients with a history of diabetes mellitus and/or with evaluable HbA1c > 6.4% were classified as having abnormal baseline glucose control. Patients with no history of diabetes and normal HbA1c were classified as having normal baseline glucose control.

Analysis
Blood glucose levels between measurements were estimated using the standard technique of linear interpolation.333435 The first value measured after MICU admission carried back to the time of admission, and the last value carried forward to MICU discharge or 120 h (whichever came first). Corticosteroid doses were expressed as hydrocortisone equivalents according to glucocorticoid effect.

Comparisons of frequencies between groups were made using a Fisher exact test. Continuous values were compared using the t test or Wilcoxon rank-sum test, as appropriate for the data distributions; p < 0.05 was considered statistically significant, while p < 0.15 suggested a trend. Models of glucose control were developed using stepwise linear regression, comparing results of backward and forward stepping for consistency; p < 0.05 was used as the criterion at each step for inclusion or removal of a covariate from a model, depending on the stepping direction. Statistical analyses were performed using NCSS 2000 (NCSS Statistical Software; Kaysville, UT).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Demographics
Eight patients with APACHE II scores < 12 were excluded from analysis. Of the remaining patients, 88 patients had blood available for HbA1c testing. HbA1c samples were obtained a median of 1 day (quartile boundaries, 0 days and 1 day) after MICU admission. Thirteen patients received ≥ 2 U of RBCs prior to the HbA1c analysis, and were therefore classified as having indeterminate baseline glucose control.

Of the 75 patients with analyzable data including interpretable HbA1c, 15 patients had a history of diabetes. Nine other patients without history of diabetes had HbA1c > 6.4%. These 24 patients were classified as having abnormal baseline glucose control. The remaining 51 patients had HbA1c levels ≤ 6.4%, and constitute the group considered to have normal baseline glucose control.

Among patients with evaluable HbA1c, there was only a weak correlation between HbA1c and BMI (p = 0.07, R2 = 0.04). Removal of patients with previously known diabetes from the analysis slightly strengthened this relationship (p = 0.05, R2 = 0.07). Among patients with normal baseline glucose control, there was no evidence of a relationship between HbA1c and BMI (p > 0.35).

Respiratory insufficiency and neurologic dysfunction were manifest in most patients within the first 24 h of MICU admission, and renal insufficiency and sepsis were evident in nearly half (Table 1 ). Acute cardiac conditions were uncommon. The group with normal baseline glucose control differed markedly from the group with abnormal baseline control only with regard to HbA1c (p < 0.001). There was a trend toward higher BMI in the group with abnormal baseline control (p = 0.14). Demographics, organ dysfunctions at MICU admission, and severity of illness were similar between the two groups. The 17 patients with unknown or uninterpretable HbA1c were similar to the other patients, but had higher APACHE II scores and had received substantially more blood. Data summarizing therapeutic interventions tested for association with hyperglycemia are listed in Table 2 .


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  		Table 1.. Demographics of ICU Patients by Baseline Glucose Control, as Determined by HbA1c and History*

 

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  		Table 2.. Therapeutic Interventions*

 
The median ICU stay was 7.4 days (quartile boundaries, 3.8 days and 16.7 days), and the median hospital stay was 15.2 days (quartile boundaries, 8.3 days and 28.8 days). Sixty-five patients (71%) survived to discharge from the MICU, and 53 patients (58%) survived to hospital discharge. Patients with normal and abnormal baseline glucose control had similar lengths of stay and survival rates.

Propensity for Hyperglycemia
Hyperglycemia was seen routinely. Only four patients, with 3 to 11 glucose measurements apiece, were never observed to be hyperglycemic (glucose > 110 mg/dL). Two of these patients had normal baseline glucose control, one patient had no history of diabetes and no blood available for HbA1c testing, and one patient had HbA1c of 6.9% without history of diabetes.

Hyperglycemia appeared early in the MICU admission. The initial measurement of blood glucose after MICU admission (median, 2.3 h after admission) was > 110 mg/dL in 59 patients (64%), > 150 mg/dL in 35 patients (38%), and > 200 mg/dL in 21 patients (23%). Patients with abnormal baseline glucose control had higher initial, peak, and average blood glucose levels than patients with normal baseline glucose control (Table 3 ). Most patients in both groups were hyperglycemic > 90% of the time, but patients with abnormal baseline glucose control spent significantly greater fractions of their initial ICU stay above other, higher glycemic thresholds than did patients with normal baseline control (Table 3, Fig 1 ). For example, the median patient with abnormal baseline control had blood glucose > 200 mg/dL 40% of the time, compared to 2% of the time in the median patient with normal baseline control (p < 0.007).


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  		Table 3.. Glucose Control Following MICU Admission*

 


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  		Figure 1.. Median percentages of time in the first 120 h of MICU admission that patients with evaluable baseline glucose control were above glycemic thresholds.

 
Hyperglycemia in Patients With Normal Baseline Glucose Control
Among patients with normal baseline glucose control, univariate analysis found the fraction of time spent hyperglycemic was associated with HbA1c (p < 0.006, R2 = 0.15), with time hyperglycemic increasing by 19% for each 1% increment in HbA1c. Average glucose and the fraction of time glucose > 150 mg/dL were also significantly associated with HbA1c in this group (p < 0.05 for each). Peak glucose and the fractions of time glucose was > 200 mg/dL, > 250 mg/dL, and > 300 mg/dL all trended with HbA1c (p < 0.15 for each) [Fig 2 ].



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  		Figure 2.. Percentages of time (median and quartile bounds) over glucose thresholds within the first 120 h of MICU admission, comparing low normal, high normal, and abnormal baseline glucose control.

 
Other factors analyzed for their relationship to the fraction of time patients with normal baseline glucose control were hyperglycemic included age, gender, BMI, presence of an inflammatory state, APACHE II score, and time averaged doses of corticosteroids, IV dextrose, enteral carbohydrates, norepinephrine, and propofol. Of these, only enteral and IV carbohydrate doses were clearly associated with hyperglycemic time (p < 0.05 for each), while a trend was observed for age and corticosteroid dose (p < 0.15 for each). Forward stepwise linear regression, including all factors as potential covariates, found HbA1c, age, corticosteroid dose, IV dextrose dose, and enteral carbohydrate dose to be independent predictors of hyperglycemic time (p < 0.05 for each, total R2 = 0.49) [Table 4 ], with HbA1c the first covariate entering the model. Backward stepping produced the same results. The relationship of HbA1c with hyperglycemic time (12% increase in time for each 1% increment of HbA1c) was similar to that found on univariate analysis.


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  		Table 4.. Independent Predictors of Fraction of Time Hyperglycemic Among Patients With Normal Baseline Glucose Control

 
Multiple linear regression with stepwise selection identified HbA1c, IV dextrose dose, and norepinephrine dose as independently related to both peak blood glucose (total R2 = 0.45) and average blood glucose (total R2 = 0.33). Similarly, HbA1c, corticosteroid dose, IV dextrose dose, and norepinephrine dose were independent predictors of the fraction of time glucose was > 150 mg/dL (total R2 = 0.34).

Time spent above higher glycemic thresholds was less predictable, perhaps because of frequent intervention with insulin as hyperglycemia worsened. Only HbA1c and norepinephrine dose were independently associated with the time glucose was > 200 mg/dL (total R2 = 0.18). No covariates were predictive of the fraction of time glucose was > 250 mg/dL, while BMI and norepinephrine dose were independently associated with the fraction of time glucose was > 300 mg/dL (total R2 = 0.19). In all regressions, forward and backward stepping yielded identical models.

Stability of HbA1c During Critical Illness
Blood was available for a second HbA1c assay in 30 patients. Three patients received RBC transfusions between HbA1c measurements. In the 27 remaining pairs, obtained 4.3 ± 1.3 days (mean ± SD) apart, HbA1c changed 0.0 ± 0.3%. The median absolute change was 0.1%. In the population with initially normal HbA1c and evaluable paired samples, there was no meaningful relationship between HbA1c change and average blood glucose (p > 0.5), with the two negatively correlated (R = – 0.12).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
Hyperglycemia was a nearly universal occurrence in this severely ill population of medical patients. Most patients were hyperglycemic most of the time. This is, to our knowledge, the first investigation to document this phenomenon in a medical population not specifically having acute vascular disease. Our population was chosen for anticipated length of stay as well as acuity, and thus provides an opportunity to reduce time exposure to hyperglycemia.

The severity and frequency of hyperglycemia during critical illness is determined in part by acute stimuli, including corticosteroids, exogenous catecholamines, and carbohydrates. However, we found that blood glucose regulation prior to critical illness was as important as any stimulus. Even among patients with normal baseline glucose control, higher (but still normal) HbA1c was associated with more frequent and severe hyperglycemia. During critical illness, the usual correlation between HbA1c and plasma glucose34 is shifted, presumably through loss of homeostatic reserve.

Surprisingly, severity of illness, as measured by the APACHE II score (or its acute physiology component), was not associated with either the degree or duration of hyperglycemia. Critical illness is clearly associated with hyperglycemia, as evidenced by its near universality in both our population and others.25 A statistically significant relationship between insulin requirements and APACHE II score has been found in a predominantly post-thoracic surgical ICU population,24 a population markedly less ill than that we studied. Less severe acute illness also has been associated with hyperglycemia, though to a lesser degree.36 Our findings, combined with these others, imply a saturation effect of illness severity on glucose dysregulation, somewhere between the illness level of a general ward and that represented by an APACHE II score of 12.

We believe the association in nondiabetics between HbA1c and hyperglycemia during critical illness results from stressing normally adequate homeostatic mechanisms: patients with the greatest baseline reserve, as reflected by HbA1c, have less hyperglycemia. Other possible explanations for our findings, including patient misclassification, acute alterations in hemoglobin-glucose binding kinetics, and changes in erythrocyte life span, seem improbable.

The diagnosis of preexisting diabetes in critically ill patients is limited to clinical history and HbA1c. Diabetes is usually identified using fasting glucose levels and, less frequently, oral glucose tolerance testing.37 Neither are available during acute illness, and testing after recovery has several limitations. Nonsurvivors cannot be assessed, removing the sickest patients from analysis. Also, later tests may not be reflective of glucose regulation before critical illness. Protracted changes in body composition, and perhaps endocrine function, following severe illness may alter glucose homeostasis.

Lacking applicable standards, we defined normal baseline glucose control as normal HbA1c and the absence of a diabetic history. Other investigators1131 have reported that up to 25% of patients with acute myocardial infarction, a group with disease epidemiologically linked to diabetes, have previously undiagnosed diabetes. As only 8% of our patients had active cardiac disease, their prevalence of undiagnosed diabetes was likely lower. The specificity of HbA1c for diabetes is > 80%38; of 60 evaluable patients without a history of diabetes, we excluded 15% because of elevated HbA1c. Our misclassification rate in the normal glucose control group should therefore be not > 14%, and is likely lower.

It seems doubtful that a critical illness associated increase in hemoglobin-glucose reaction kinetics underlies our findings. HbA1c would then be a surrogate for average plasma glucose over a relatively short time interval, reflecting recent homeostasis rather than baseline control. However, almost all patients were hyperglycemic relative to their HbA1c-predicted average plasma glucose levels.34 Increased reaction kinetics would have resulted in rising HbA1c during the first few days of the ICU stay, with the increase corresponding to the average plasma glucose. No such trend was observed among patients with evaluable paired HbA1c samples.

Finally, reduced erythrocyte survival time seems an unlikely explanation for the relationship between HbA1c and hyperglycemia during critical illness. Hemoglobin glycosylation occurs throughout the life span of erythrocytes, and patients with disorders leading to reduced average erythrocyte age have correspondingly low HbA1c fractions.394041 If our patients’ erythrocytes were relatively young, it might have shifted undiagnosed diabetic patients into the upper portion of the normal HbA1c range. The observed relationship between HbA1c and hyperglycemia during critical illness among apparent normal subjects would instead be due to unrecognized preexisting diabetes. However, critically ill patients, and particularly MICU patients, have reduced RBC production, with normal reticulocyte fractions despite anemia.4243 A particularly young erythrocyte population is thus unlikely.

Considering these arguments, we believe HbA1c retains its utility for measuring time-averaged glucose regulation in MICU patients. Among patients with normal glucose regulation at baseline, modest and nonpathologic differences in glucose homeostasis are manifest during critical illness as potentially pathologic differences in hyperglycemia.

In the population we studied, hyperglycemia was usually managed with subcutaneous regular insulin administered according to a sliding scale. Therapy was generally initiated after the plasma glucose level was > 150 mg/dL. The resultant average plasma glucose was 164 mg/dL, similar to that reported by Van den Berghe et al25 in their conventional treatment group. MICU patients have a propensity for hyperglycemia similar to a predominantly post-cardiac surgical population, despite differing pathologies. This prompts an obvious question: are there sufficient differences between these populations to confound extrapolation of Van den Berghe’s findings to MICU patients?

MICU and SICU patients do differ in important ways. For example, almost all of the mortality benefit attributable to aggressive glucose control in SICU patients stemmed from a reduction in sepsis-related deaths. Most were presumably uninfected at SICU entry, and may have benefited from the reduced wound infection rate associated with better glycemic control.164445 The patients we studied had no wounds, and nearly half presented already septic.

Our patients were more likely to present with blood glucose levels > 200 mg/dL than were the SICU patients (23% vs 12%, p < 0.005). The time exposure to hyperglycemia before MICU admission is unknown, but based on a previous survey,36 as well as the progressive illness often preceding MICU admission, we suspect it is substantial. If the advantages of tight glucose control arise from keeping patients below a threshold of hyperglycemic exposure, many MICU patients may have already missed the opportunity to benefit from therapy by the time of MICU admission. In fact, while the group was too small for adequately powered analysis, tight control exhibited a smaller mortality benefit among SICU patients with diabetes (1.8% absolute reduction), who presumably have greater pre-ICU exposure to hyperglycemia, than it did among those without diabetes (3.7% reduction).

The patients we studied were much sicker than those in the conventional treatment arm of the trial of Van den Berghe et al,25 as judged by APACHE II score (median, 22 vs 9), length of ICU stay (median, 7 days vs 3 days), and ICU mortality rate (29% vs 8%). An equivalent reduction in risk ratio in the MICU population from glucose control would make insulin a therapy of virtually unprecedented efficacy. Like many other medical intensivists, we await a more applicable clinical trial, but in the interim have elected to aggressively control blood glucose in the hope that some of the same benefits will accrue to MICU patients.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
MICU patients are prone to hyperglycemia, the severity and duration of which are associated with glucose regulation prior to the onset of critical illness. While perhaps expected when comparing diabetic with nondiabetic patients, this relationship extends to patients with normal glycemic regulation at baseline. Among the patients we studied, illness severity itself did not impact glucose regulation, suggesting a threshold effect of acuity on glucose homeostasis that patients such as ours exceed. Other factors contributing to hyperglycemia among MICU patients include carbohydrate administration, and treatment with corticosteroids and norepinephrine.

The population of patients we studied was much sicker than the SICU population in which Van den Berghe et al25 demonstrated benefit from normalization of blood glucose using insulin infusions. Significant differences with regard to blood glucose at entry, incidence of sepsis at entry, and the absence of wounds make the efficacy of this therapy in an MICU population uncertain. Further investigations into glycemic patterns during the evolution of medical critical illness, as well as an interventional trial of glycemic control in MICU patients, should both be fruitful avenues of study.


   Footnotes
 
Abbreviations: APACHE = acute physiology and chronic health evaluation; BMI = body mass index; HbA1c = hemoglobin A1c; MICU = medical ICU; SICU = surgical ICU

This work was performed at the University of Miami and Jackson Memorial Hospital, Miami, FL.

Received for publication December 11, 2003. Accepted for publication March 9, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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