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Chapter 3

Perils of Glycemic Variability and Rapid Correction of Chronic Hyperglycemia

Susan S. Braithwaite, MD,¹ and Irl B. Hirsch, MD²

¹Presence Saint Joseph Hospital, Chicago, IL; Presence Saint Francis Hospital, Evanston, IL; West Suburban Medical Center, Oak Park, IL; Westlake Hospital, Melrose Park, IL; Clinical Professor of Medicine, University of Illinois at Chicago, Chicago, IL. ²Professor of Medicine University of Washington Medical Center–Roosevelt, Seattle, WA.

DOI: 10.2337/9781580406086.03

Introduction

The objective of this chapter is to discuss evidence among hospitalized patients supporting or discrediting each of two propositions, in contexts other than hyperglycemic emergencies:

• Glycemic variability, independent of hyperglycemia and hypoglycemia, may causally contribute to risk of harm among hospitalized patients.

• Aggressive correction of chronic hyperglycemia may cause short-term harm for hospitalized patients experiencing uncontrolled diabetes.

Under each of several definitions, glycemic variability, independently from hypoglycemia and hyperglycemia, in the hospital has been recognized to be a risk factor associated with adverse outcomes.^1–12 Although supporting evidence has been collected mostly in the intensive care setting, limited data collected in the general hospital setting suggest a similar relationship.¹⁰ Glycemic variability is not restricted to patients having preexisting diabetes, whereas rapid correction of chronic hyperglycemia occurs only among patients having preexisting uncontrolled diabetes.¹ With respect to predictive value or physiology, it is not clear to what extent glycemic variability actually resembles rapid correction of chronic hyperglycemia. Therefore, we do not classify a one-time hospital-based correction of chronic hyperglycemia as an example of glycemic variability. Present-day therapeutic tools may permit the provider to control the rate of correction of chronic hyperglycemia. Importantly, we have only early evidence suggestive of therapeutic approaches that could reduce glycemic variability in the hospital.

Glycemic Variability

Glycemic Variability and Outcomes in the Inpatient Setting

The goal of this section is to discuss evidence that harms occurring in the hospital are associated with glycemic variability, independent of hyperglycemia and hypoglycemia (Table 3.1). The definition of variability and choice of metrics may determine whether or not a pattern of glycemia within a population is identified as showing increased patient-level glycemic variability.^2–12 Intuitively, for this discussion, glycemic variability is understood as a propensity of a single patient to develop repeated episodes of excursions of hyperglycemia or troughs of hypoglycemia over a relatively short period of time that exceed the amplitude expected in normal physiology.¹³

Table 3.1—Outcomes Associated with Glycemic Variability

*At least 3 BG measurements were required.

See also Braithwaite.¹³

To characterize or compare groups of patients, it is desirable to choose metrics that will quantify the variability experienced by typical group members. The choice of metrics used to identify variability has been controversial. When standard deviation (SD) or coefficient of variability (CV) is used as a variability metric, all of the data points are used, thus optimizing the power of the metric to make comparisons. For inferential or predictive purposes, SD should be applied to data sets exhibiting Gaussian distribution. Recognizing the predictive value of CV with respect to risk for hypoglycemia, and depending on whether the absolute magnitude of excursions is important or the magnitude of excursions relative to the mean, some authorities favor CV over SD.^14,15 The SD is highly correlated with the mean BG.¹⁶ In a study of 18,563 patients having myocardial infarction, an association of variability with mortality risk, noted by five metrics in unadjusted analyses, was not upheld after reexamination with adjustment for patient factors, including mean BG.⁷ Recognizing that a single major change of glycemia during an observation interval can yield a high SD, we favor caution on the use of the SD or CV during intervals of rapidly changing average of blood glucose. Alternative metrics should be considered, such that glycemic variability can be differentiated by the chosen metrics from rapid correction of chronic hyperglycemia.^5,13 Nevertheless, some of the earliest and strongest evidence linking variability to outcomes in the critical care setting is based on the use of SD.^2,3

During an era in which the inpatient use of continuous glucose monitoring (CGM) has not yet become a standard of care, the study of inpatient glycemic variability has suffered from irregularity of timing and infrequency of monitoring of blood glucose. When applied to CGM, the problem of autocorrelations introduces a caveat for the use of SD with traditional statistics. Kovatchev and Clarke¹⁷ report that the autocorrelation coefficients become insignificant at a time lag of approximately 1 h, such that CGM readings more than 1 h apart could be considered linearly independent.

Outcome studies about variability in the hospital generally confirm an association of variability, identified by at least some measures, with adverse outcomes. Although variability is associated with hyperglycemia and hypoglycemia, in multivariate analyses, variability has remained an independent predictor of adverse hospital outcomes.^6,8 The outcomes have included nosocomial infection rate, hospital length of stay, and mortality.¹³ The relationship between glycemic variability and outcomes in the hospital may be stronger among patients not having known diabetes than among those with diagnosed diabetes and, depending on the study, may be attenuated or not discernable in the presence of diabetes.^4,9–11 As a caution on interpretation, it is noted that a one-time correction of BG with insulin during the time frame of data collection may inflate the SD or CV, thus complicating comparisons of these metrics among patients who did or did not experience such one-time corrections of overall glycemia. Additionally, in the analysis of large groups, it is likely that patient factors should be considered that may acutely change overall glycemia and degree of insulin resistance, including underlying diagnosis, use of glucocorticoids, nutritional treatment plan, and choice of antihyperglycemic therapy.

Technology and newer treatments may be at hand that have the potential to reduce glycemic variability, thus permitting both design of randomized trials and ultimately therapeutic intervention to reduce variability.^18–21 The expected opportunities for improvement include refinement of insulin-based treatment algorithms, hypoglycemia protocols, use of glucose monitoring technology to improve the effectiveness of insulin delivery systems,²² new insulins, and use of incretin-based therapy.²³

Glycemic Targets and Rate of Correction

As is well appreciated, the strongest evidence showing causal relationship between hyperglycemia and complications of diabetes arose from randomized trials of the 20th century, including the Diabetes Control and Complications Trial Research Group (DCCT) and UK Prospective Diabetes Study (UKPDS), enrolling patients having type 1 diabetes (T1D) and type 2 diabetes (T2D), respectively.^24,25 These trials demonstrated, in comparison to control groups receiving less intensive treatment, that there was reduction in the risk of microvascular complications for patients receiving more intensive glycemic management. Each intensively treated group experienced a greater event rate for hypoglycemia. Reductions in the microvascular complications in these studies are thought to result from exposure to hyperglycemia experienced over the long term, in time frames measured in years (also termed “glycemic exposure”). A separate question is whether immediate beneficial consequences of glycemic exposure, in the absence of a hyperglycemic emergency, also would be realized by hospitalized patients vulnerable to a different set of specific risks that potentially would be realized in the short term. Theoretically, the improvement of hyperglycemia and glycemic variability could reduce reactive oxygen species accumulation and inflammatory activation, resulting in both short-term and long-term benefits.

Glycemic Targets and Rate of Correction in the Ambulatory Setting

In the ambulatory setting, during initial correction of chronic hyperglycemia, a patient may experience painful neuropathic symptoms.^26–30 Similarly, during intensification of therapy, early worsening of retinopathy may be observed. Risk factors for early worsening include the duration of diabetes, severity of the diabetic retinopathy at baseline, higher HbA_1c, and magnitude of HbA_1c reduction, such that specific cautions on monitoring have been recommended.^31,32 The temporary problems of acute painful sensory neuropathy or early worsening of retinopathy are seen as a tolerable price to pay for the long-term benefits expected from improved glycemic control. In the ACCORD trial, however, in an older population with more cardiovascular disease than among subjects studied in the UKPDS, intensification of therapy of T2D was accompanied by increased mortality.^33–35 With acknowledgment that mechanisms of harm would be different in each situation, and that comorbidities and concomitant therapies must be considered, these experiences are mentioned as analogies when discussing whether treatment guidelines for hyperglycemia in the inpatient setting might differ according to the presence or absence of diabetes. Furthermore, among patients with diabetes, one needs to consider whether the target and rate of correction of hyperglycemia might differ according to severity of chronic hyperglycemia before admission, as reflected by the HbA_1c or other indicators of preadmission control, including other biomarkers, such as fructosamine, glycated albumin, home blood glucose monitoring, or CGM. As we enter the era of personalized medicine, it is quite possible that glycemic targets may differ based on the preexisting metabolic status of the patient.

Glycemic Targets and Rate of Correction among Subgroups of Hospitalized Patients

Many observational studies of hyperglycemia in the hospital setting include both patients with diabetes and patients not known to have diabetes. Overall, the findings show that hospital hyperglycemia is associated with adverse outcomes, including mortality (see Chapter 1).³⁶ If diabetes can be discounted, then hospital hyperglycemia may be designated as stress hyperglycemia.³⁷ In the critical care setting, randomized trials of strict glycemic control have not produced consistent evidence for benefit among mixed intensive care unit (ICU) populations, but overall these trials have demonstrated increased risk for hypoglycemia. In some but not all reviews or meta-analyses of interventional trials among critically ill patients, a signal suggesting benefit persisted according to subpopulation, with beneficial outcomes most readily observable among surgical patients.

Relationship of Outcomes to Hyperglycemia in the Presence of Diabetes

In some but not all observational studies of patients confirmed to have diabetes, the severity of hyperglycemia at the time of admission or during the course of hospitalization has been found to correlate with adverse outcomes. Among surgical patients, an increased risk of surgical site infection, myocardial infarction, stroke, and death, associated with the presence of diabetes, has been thoroughly reviewed.³⁸ There have been exceptions to a general observation that severity of chronic hyperglycemia may be associated with adverse surgical outcomes. Among surgical patients with diabetes, however, most studies reporting glucose levels before elective surgery, or preoperative HbA_1c, do find a relationship between severity of chronic hyperglycemia and adverse outcomes. Despite the lack of randomized controlled trials that might define any impact of preoperative correction of hyperglycemia, guidelines have been issued suggesting an upper limit of acceptable HbA_1c between 8 and 9% before elective procedures.³⁹ However, there is no true consensus on this point.

Over the years during which health-care-provider protocols for the reduction of perioperative hyperglycemia were increasingly utilized in patients with diabetes having cardiothoracic surgery, a downward trend was noted for adverse outcomes in the population having diabetes (see Chapter 1).³⁶ During the same time frame, however, other aspects of care also changed. Although studied prospectively, much of the data in the cardiac surgery population with diabetes has been observational, such that a clear causal relationship between attainment of specific glycemic targets and improvement of outcomes cannot be inferred with confidence.

Outside of the ICU, an effective glycemic treatment protocol among surgical patients with diabetes also signaled a benefit. Some of the benefits included reduction of infection, reoperation, and mortality. A randomized trial among general surgical patients with T2D showed improvement of a composite end point of postoperative complications, including wound infection, pneumonia, bacteremia, and respiratory and acute renal failure.⁴⁰

Among noncritically ill admissions with T2D having a cardiac or infection-related diagnosis, a recent retrospective analysis of the impact of glycemic control on hospital outcomes of 378 patients was divided into two groups according to mean point-of-care glucose for evaluation of adverse events, including death during hospitalization, ICU transfer, initiation of enteral or parenteral nutrition, line infection, new in-hospital infection, or infection lasting >20 days of hospitalization, deep venous thrombosis or pulmonary embolism, qualifying rise of creatinine, or readmission. In the group having mean BG <180 mg/dL, there were lower SD of BG and lower admission HbA_1c, with overall 1.00 events per patient, compared with 1.46 (P < 0.0004) for the group with mean BG ≥180 mg/dL.⁴¹

Comparison of Stress Hyperglycemia and Diabetes

In studies that classify hyperglycemia according to presence or absence of chart history of diabetes or preadmission antihyperglycemic medication use, some hyperglycemic patients will have diagnosed or undiagnosed diabetes and others will have stress hyperglycemia. A study of burn patients showed greater length of stay for burn victims admitted with diabetes compared with those who had acute hyperglycemia.⁴² A meta-analysis of observational and interventional studies between May 2005 and May 2010 involving 12,489,574 critically ill patients, of whom 2,327,178 had diabetes, suggested increased mortality among patients with diabetes and admitted to the surgical ICU, with odds ratio (OR) for ICU mortality (95% confidence interval [CI]) being 1.48 (1.04 to 2.11), in-hospital mortality 1.59 (1.28 to 1.97), and 30-day mortality 1.62 (1.13 to 2.34). Otherwise, in this meta-analysis, the presence of diabetes showed no overall association with mortality.⁴³ In the general critical care setting, a number of studies have found that diabetes itself is not a predictor of increased mortality.^9,42,44–47 In many studies, hyperglycemia without a history of diabetes has been associated with outcomes worse than those outcomes observed among patients known to have diabetes.^9,38,48–56 In a seminal report, although mean BG on admission of 223 patients with new hyperglycemia did not differ significantly compared with that of 495 patients with known diabetes, higher hospital mortality was observed in the new hyperglycemia group.⁴⁸ Details of studies contrasting the impact of diabetes versus stress hyperglycemia upon outcomes are shown in Table 3.2.

Table 3.2—Outcomes Associated with Diagnosis of Diabetes, Compared to Stress Hyperglycemia, in Relation to Hyperglycemia

Some studies refine the comparison between stress hyperglycemia and diabetes by focusing on given levels of hyperglycemia, which may be associated with harms experienced among patients not having diabetes, and which may be associated with less risk among those known to have diabetes. Among 8,727 cardiac surgery patients, when the adjusted ORs for specific complications were considered at each of three bands of glycemia (good, moderate, or poor control) according to the presence or absence of diabetes, the difference in complication rates between those having or not having diabetes was greatest for those with poor BG control (peak glucose >250 mg/dL in the first 60 h postoperatively), such that the diabetes group had the lower rate for each type of several complications (see Figure 3.1).⁵²

Figure 3.1—Prevalence of complications by blood glucose concentrations and diabetes status.

Source: With permission from Ascione et al.⁵²

In a case-control single-center ICU study, after implementation of an insulin-based glycemic management protocol for BG >150 mg/dL, the rate of death in the hospital was 10% (95% CI, 9–12%) for patients without diabetes who required glycemic control, higher than the rate of 6% (95% CI, 4–7%) for patients with diabetes, or 5% (95% CI, 4–6%) for controls (P < 0.001). Mortality increased for patients without diabetes at mean blood glucose of 144 mg/dL and for patients with diabetes at 200 mg/dL (P < 0.001).⁴⁹ In another mixed ICU study, when glucose readings were examined by several metrics among 4,946 admissions, the degree of hyperglycemia was found to be associated with mortality among the patients without diabetes but, at similar levels, not among the 728 patients with diabetes. Hyperglycemia showed no significant association with outcome in the patients with diabetes.⁵³ Under some methods of analysis, hyperglycemia in the presence of diabetes even may seem to confer a “protective” effect when compared with similar degrees of hyperglycemia in the control population.^38,52,55 In a large multicenter international observational study of 44,964 patients admitted to 23 ICUs with 12,880 patients identified as having diabetes, diabetes was associated independently with a slightly lower mortality rate, with OR (95% CI) of 0.93 (0.87–0.97); among patients with mean BG 80–110 mg/dL, diabetes was independently associated with increased risk of mortality, but among patients with mean BG of 110–140 mg/dL, diabetes was independently associated with decreased risk of mortality, leading the authors to speculate that those with antecedent diabetes may have developed a tolerance for hyperglycemia that was lacking among those experiencing stress hyperglycemia.⁹

Of course, such an interpretation that diabetes confers a “protective effect” implies that hyperglycemia as a stress response does itself contribute to adverse outcomes. Another speculation, more relevant on general wards, would be that the beneficial actions of insulin are more likely to be experienced by patients with diabetes, because of greater readiness to introduce insulin therapy.^38,57 Difficulty of interpretation results from the observational design of most studies. There is uncertainty on diagnosis of diabetes in some reports; uncertainty whether stress hyperglycemia in general is simply a marker of severity of illness or other downstream consequence of the illness or its treatment, possibly even beneficial⁵⁸; and, conversely, uncertainty whether stress hyperglycemia at some given level of severity becomes maladaptive, itself contributing to adverse outcomes.

It has been suggested that stress hyperglycemia may be no worse a prognostic indicator than lactate levels. The incremental overall increase of lactate observed in hospitalized populations with stress hyperglycemia is so small that measurements would be incapable of discriminating between normal or stressed physiology in most individual cases. Still, lactate levels have been shown to correlate with outcomes, in a manner similar to stress hyperglycemia.^59–61 An emergency room follow-up study of patients with sepsis found that mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia.⁶⁰ In one retrospective ICU study, no independent association between hyperglycemia and mortality was identified, once lactate levels were considered.⁶²

Optimal Control of Hospital Hyperglycemia in the Presence of Diabetes

It is unknown what the optimal targets for glycemic control should be for subgroups of hospitalized patients with the diagnosis of diabetes along with another admitting diagnosis. When pooled data of critically ill medical and surgical patients from Leuven, Belgium, were studied, no mortality reduction from intensive control was demonstrable in the subgroup with diabetes.⁶³ Examining mortality in relation to bands of glycemia, a recent large multicenter observational study of critically ill patients found that among patients without diabetes, the lowest mortality rate was seen with a mean BG 80–140 mg/dL, whereas the lowest mortality among those with diabetes was seen at mean BG 110–180 mg/dL.⁹

It has been speculated but not proven that rapid reduction to low targets may be harmful for those patients with diabetes who have become acclimatized to chronic hyperglycemia. The speculation is based partly on a two-center ICU observational study of 415 ICU patient with diabetes, showing that if time-weighted hospital glycemia was in a higher rather than lower range, then patients with diabetes with higher HbA_1c (>7%) had a lower mortality rate than those with diabetes with lower HbA_1c (≤7%) (see Figure 3.2).⁶⁴ For those with HbA_1c >7%, among the nonsurvivors, there was a lower time-weighted average BG than among the survivors. At lower HbA_1c, the mortality difference according to time-weighted average BG was not apparent. The authors speculated that rapid reduction of hyperglycemia, among patients habituated to chronic hyperglycemia, might be acutely harmful. By not capturing the glucose on first admission to compare against the HbA_1c, however, the effects of medical stress could have been underestimated.⁶⁴

Figure 3.2—Among patients having diabetes and admitted to intensive care units, odds ratios for hospital mortality are shown comparing those with higher (>7%) versus lower (≤7%) HbA_1c, according to time-weighted average of blood glucose control in mMol/L.

Source: From Egi et al.⁶⁴

Among patients with diabetes, it may be necessary to differentiate between those admitted with chronic hyperglycemia and those experiencing acute worsening of hyperglycemia upon admission, whose physiology might more closely resemble that of a person having stress hyperglycemia. The abnormalities of physiology that might cause stress hyperglycemia also may exist in a patient with diabetes. Among patients with diabetes, little published information examines outcomes separately for those with or without exacerbation of preadmission glycemic control, which might be taken as the equivalent of stress hyperglycemia among patients with diabetes.

It must be acknowledged that exacerbation of hyperglycemia in diabetes is not readily definable in a quantitative manner that would permit comparison to stress-induced hyperglycemia among people without diabetes. When HbA_1c results are considered, hyperglycemia detected during admission may have the greater adverse prognostic significance among those patients with diabetes who formerly had the more satisfactory control.^64–67 Although the numbers of patients examined so far has been small, a great step forward is taken by those studies that refer to HbA_1c to identify acute changes of glycemia, including rapid reduction or stress-induced exacerbation of hyperglycemia among patients with diabetes, and their relationship to outcomes (Table 3.3). In a study of mortality among patients having known diabetes admitted with pneumonia, the 30-day mortality was not predicted by admission glucose, hypoglycemia during hospitalization, or HbA_1c, but rather was predicted by mean glucose during the admission.⁶⁵ In an observational study of 329 pyogenic liver abscess patients with diabetes, the HbA_1c alone did not predict adverse outcomes. Among 131 patients having available both an HbA_1c within 1 week of admission and also an evaluable admission BG, the “glycemic gap” (admission BG minus estimated average BG) was shown to be associated with adverse outcomes. In a receiver operating characteristic (ROC) analysis, a glycemic gap cutoff value of 72 mg/dL was optimal for predicting adverse outcomes.⁶⁶ One center has shown that among patients with diabetes, peak glucose predicts adverse ICU outcomes for those having lower HbA_1c, but not for those having higher HbA_1c (see Figure 3.3).⁶⁷ The study of 1,000 critically ill patients showed significantly higher mortality for those having diabetes with HbA_1c >7%, but no relationship to peak hyperglycemia. Among the patients with HbA_1c <7% and those having stress hyperglycemia, the mortality risk increased according to severity of peak hyperglycemia in the first 48 h. In a multivariable analysis, however, these relationships no longer were seen, and only the Acute Physiology and Chronic Health Evaluation II (Apache II) score was independently associated with mortality.⁶⁷ In a search for metrics that might be used to assess the importance of exacerbation of both acute and chronic hyperglycemia, the stress hyperglycemia ratio (SHR) has been defined by one group as the ratio of admission glucose divided by estimated average glucose derived from HbA_1c.⁶⁸ From a study population of 4,691 admissions of adult nonobstetric patients, in a multivariable analysis containing glucose, SHR, and other defined variables, higher values for the SHR, but not for glucose, were found to be independently associated with critical illness (either in-hospital death or admission to the ICU). From the finding of a single elevation of admission HbA_1c, the authors did not diagnose diabetes but rather identified patients as having background hyperglycemia.⁶⁸ None of these studies attempted to infer the likely presence of stress-induced exacerbation of hyperglycemia by the company it might keep, such as increased lactate levels.

Table 3.3—Glycemic Gap: Hospital Complications among Patients Confirmed to Have Diabetes, in Relation to Acute Hospital Hyperglycemia

*Glycemic gap = difference between HbA_1c-derived estimated average glucose (eAG) and observed plasma glucose measured at initial presentation.

See also a discussion of “background hyperglycemia” in relation to acute hospital hyperglycemia.⁶⁸

Figure 3.3—Hospital mortality versus acute glycemia according to preadmission HbA_1c in critically ill patients. Open circles, no diabetes or stringently controlled (HbA_1c <6%); open squares, diabetes (HbA_1c 6–<7%); closed diamonds, (HbA_1c ≥7%).

Source: From Plummer et al.⁶⁷

Attempts have been made to infer the prevalence of diabetes from sampling of HbA_1c upon admission to the hospital.⁶⁹ Even in the ambulatory setting, many intercurrent conditions may affect the HbA_1c, so as to invalidate its utility in diagnosing diabetes or assessing glycemic control. Factors such as anemia, transfusions, renal disease with or without use of erythropoietin, and other conditions may be even more prevalent among hospitalized patients. Although we believe it is premature to embrace specific targets based on the absence of diabetes or admission HbA_1c in the presence of diabetes, it is noted that Marik and Egi have suggested a spectrum of therapeutic targets for each of six categories of ICU patients.^1,70

The Paradox of the Protective Effect of Diabetes: Fact or Artifact?

When the evidence is considered that diabetes may be a risk factor for some adverse outcomes, but that a given level of hyperglycemia is more strongly associated with harms for patients not having diabetes than for those with diabetes, then a paradox would appear to be presented.^38,71 The paradox arises from comparison of outcomes at comparable bands of hyperglycemia between those hyperglycemic patients with or without diabetes. Kotagal et al. examined possible explanations for the seeming paradox and have suggested that one likely contributing factor, among several suggested explanations, could be that insulin therapy is more consistently and better delivered in patients with a known diagnosis of diabetes and that insulin therapy is less well tolerated when delivered to those not having diabetes.^38,57 Another interpretation acknowledged by Kotagal et al.³⁸ and others^9,67 deserving consideration here could be that habituation to and tolerance of chronic hyperglycemia may occur for patients with diabetes, in contrast to intolerance that may be experienced by patients rendered acutely hyperglycemic who formerly did not have diabetes.⁴⁷ Another highly plausible possibility could be that a given level of hyperglycemia for a patient not having diabetes may signify greater physiologic stress than for a patient with diabetes. In fact, some of the hyperglycemic group members cataloged as not having diabetes may in fact have had unrecognized diabetes.³⁸ HbA_1c, for example, is often falsely low in patients who have chronic illness and it may be impossible to have an accurate glycemic history for those patients.⁷²

In describing the effect of hyperglycemia upon outcomes among patients with diabetes, we are reluctant to accept the terms “paradox” or “protective,” because we lack knowledge of the appropriate comparative groups of patients. Those who would advocate more lenient targets for patients who have diabetes with hyperglycemia generally have argued that the hyperglycemia may be protective or that acute reduction may be poorly tolerated. Given that stress hyperglycemia is recognized to have prognostic significance among people who do not have diabetes, it seems desirable to recognize stress-induced exacerbation of hyperglycemia among patients with diabetes. We suggest that outcomes for the following groups be considered separately, not only looking at observational studies but also, using effective technologies, eventually randomizing with the intent to treat to specific targets:

• No diabetes, no stress hyperglycemia

• No diabetes, stress hyperglycemia

• Diabetes, lacking stress-induced exacerbation of hyperglycemia, or lacking physiology of stress hyperglycemia

• Diabetes, having stress-induced exacerbation of chronic hyperglycemia, or having physiology of stress hyperglycemia

Additionally, it is important to recognize other physiologic markers such as lactate elevation and to include adjustment for severity of illness such as the Apache II score in comparative analyses. It is conceivable, although not specifically suggested by the evidence, that some form of “early worsening” could result from overly aggressive correction. Randomized trials would be needed to attempt to discern optimal levels of glycemia in relation to preadmission glycemic control of diabetes, according to comorbidities.

We believe that advances in technology for monitoring and treatment may improve our ability to achieve and maintain specific targets, permitting effective randomization in clinical trials that are designed to test hypotheses related to condition-specific assignment of glycemic targets.^1,73 After further study, if the impression that hyperglycemia should be approached cautiously according to preadmission HbA_1c elevations is upheld, then one approach would be that hospitalized patients with uncontrolled diabetes should have higher glycemic targets for the short term than other patients hospitalized with the same conditions. An alternative approach would be that the universal targets, if applicable, should be approached more slowly for patients with uncontrolled diabetes. On the other hand, a strong case can be made that before elective surgery, glycemic control should be optimized safely, in the ambulatory setting.

Table 3.4

Patient group	Therapeutic blood glucose target, mg/dL
Without diabetes	140–200
With diabetes, HbA1c <7%	140–200
With diabetes, HbA1c ≥7%	160–220
Cardiac surgery, without diabetes	140–180
Cardiac surgery, with diabetes, HbA1c <7%	140–180
Cardiac surgery, with diabetes, HbA1c ≥7%	160–200

Conclusion

Observational data suggest that glycemic variability may be an independent predictor of adverse hospital outcomes. To confirm a causal relationship between variability and outcomes, interventional trials are required that have the capability of randomizing patients to greater or lesser variability while maintaining similar mean glycemia. Methods for future research and treatment might include improvements in glycemic monitoring and insulin delivery algorithms, as well as non-insulin-based therapeutic interventions, including incretin-based therapies. It is hoped that improvement in therapeutic regulation of glycemic control will be capable of reducing glycemic variability. Importantly, at the present time, providers may have relatively little control over glycemic variability.

In contrast, the actions of providers may determine whether or not patients experience acute correction of chronic hyperglycemia. In the presence of diabetes, chronic hyperglycemia may increase the risk for adverse outcomes, especially for patients considering elective surgery. For some outcomes among critically ill populations, however, the impact of chronic hyperglycemia in the presence of diabetes may be less than the impact of stress hyperglycemia of comparable magnitude among patients without diabetes. Any mechanisms of harms from rapid correction are unknown at this time, but they would not necessarily be limited to harms of the concomitant risk of hypoglycemia. Harms from rapid correction of chronic hyperglycemia are not yet proven to outweigh potential benefits. The balance between harms (if any) and benefits of rapid correction of chronic hyperglycemia are likely to differ according to comorbidities, concomitant therapies, site of care, and the underlying reasons for admission.

We conclude that it is premature to establish specific cautionary guidelines about the correction of chronic hyperglycemia for hospitalized patients with diabetes, but acknowledge evidence suggestive that these guidelines could differ from recommendations for the general population. Analysis will be complex, with due consideration for the importance of glycemic control to concomitant medical conditions, in the presence of diabetes. A take-home message may be that caregivers should “stay tuned” to personalized glycemic targets in the hospital and, for now, should ascertain the HbA_1c or indicators of preadmission glycemic control and at least consider the results when individualizing patient care plans.

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