Chapter 74: Controversies: Is Glucose Control Relevant?

Virtually all adult medical ICU patients experience at least 1 blood glucose value above the normal fasting level (110 mg/dL).¹ The stress of critical illness promotes a state of insulin resistance which is characterized by increased hepatic gluconeogenesis and glycogenolysis, impaired peripheral glucose uptake, and higher circulating concentrations of insulin. There is upregulation of hepatic glucose production triggered by elevated levels of cytokines and counterregulatory hormones such as glucagon, cortisol, growth hormone, and catecholamines. These metabolic disturbances together with common ICU treatments such as corticosteroids, sympathomimetic agents, and glucose-containing infusions explain the frequently observed phenomenon of hyerglycemia irrespective of the disease, diabetes mellitus.

Many practitioners have viewed moderately severe hyperglycemia among critically ill patients to be either an epiphenomenon or an adaptive response, not warranting significant concern or intervention.

Large observational studies in different types of ICU populations reveal a J-shaped relationship between blood glucose levels and mortality of critical illness, with the mortality nadir somewhere between 80 and 140 mg/dL depending on the type of illness and the presence of a history of diabetes mellitus. Observations such as these raised concerns that acute hyperglycemia itself was contributing to poor outcomes, potentially by leaving affected patients susceptible to some of the complications that have long been observed among chronic diabetics, including high infection rates, poor wound healing, and polyneuropathy.

The groundbreaking Leuven I study² in 2001, conducted in critically ill surgical patients, found a remarkable overall 3.4% ICU mortality reduction, a 9.6% mortality benefit in patients with ICU LOS more than 5 days, and a 34% hospital mortality reduction in the strict normoglycemia group (target glucose 80-110 mg/dL) compared to standard therapy. These beneficial outcomes resulting from the use of intensive insulin therapy targeting normoglycemic levels sparked a strong interest in glycemic management in the ICU. Intensive insulin therapy quickly became the standard of care in both medical and surgical ICUs. However, a follow-up study, done by the same group in 2006,³ demonstrated that in contrast to the earlier study, intensive insulin therapy did not reduce overall morality and was associated with an even higher rate of serious hypoglycemia (18.7%). In the first study, it was speculated that the benefits seen were primarily due to a surgical patient population and the primary use of parenteral nutrition.

Following 4 consecutive negative trials, the most comprehensive landmark NICE-SUGAR trial⁴ results were reported. They found that the intensive insulin therapy groups achieving normoglycemia had an absolute 2.6% increase in mortality (P = 0.02) and an increased incidence of hypoglycemia (6.8% vs 0.5%). Furthermore, subsequent meta-analyses demonstrated that intensive insulin therapy provided no survival benefit and was associated with increased morbidity secondary to severe hypoglycemic episodes. These findings are also consistent with observational data reported from ICUs incorporating intensive insulin protocols as part of their hyperglycemic management. The overall consensus from the available evidence suggests that intensive insulin therapy (target glucose 80-110 mg/dL) as compared to standard insulin therapy (target glucose 140-180) does not provide an overall survival benefit, may increase mortality and is associated with a higher incidence of hypoglycemia.

Hypoglycemia has been shown in the critically ill pateint to be independently associated with a 3-fold increase in mortality. In a trial of intensive insulin therapy, severe hypoglycemia occurred in up to 28% of patients.⁵ It is further speculated that the incidence of hypoglycemia is likely to be higher outside of clinical trials if intensive insulin protocols are used. The main consequences of acute and persistent hypoglycemia are neurologic deficits, which at times can be quite difficult to detect but remain a true concern. Hypoglycemia has been shown to cause acute electroencephalographic alterations. In a 4-year follow-up of patients treated with intensive insulin therapy (target blood glucose 80-110 mg/dL), this population was found to have impairments in quality of life and social functioning as compared to patients who received conventional insulin therapy.⁶

The relationship between hypoglycemia and outcome may be explained by an association with severity of illness and an increased risk of death, or a true deleterious biologic effect in critically ill patients. Hypoglycemia might exert biologic toxicity by increasing the systemic inflammatory response, inducing neuroglycopenia, inhibiting the corticosteroid response to stress, impairing sympathetic nervous system responsiveness, causing cerebral vasodilatation or by unidentified mechanisms. Furthermore, many experimental studies have demonstrated that both insulin and hypoglycemia can induce hypotension, vasodilatation, nitric oxide release, sympathetic system response exhaustion, and decreased ability to respond to repeated stress.

The repeated observation that hyperglycemia is associated with poorer outcomes among critically ill patients, together with the theoretical harm of acutely elevated blood glucose, represents the basis for focusing on glycemic control in the intensive care setting. However, the possibility remains that elevated blood glucose levels are actually beneficial to the critically ill individual, and that stress hyperglycemia is an appropriate and adaptive response to life-threatening illness, as no randomized trial investigating glycemic control has studied the effect of truly permissive hyperglycemia.⁷

Potential benefits of hyperglycemia include promotion of glucose delivery in the face of ischemic insults (enhanced glucose diffusion gradient), with insulin resistance favoring redistribution of available glucose stores toward cells of the immune and nervous systems, and away from peripheral tissues. Recent observational studies have provided some support for this view, reasserting the possibility that hyperglycemia is simply a marker of illness severity when controlled for hyperlactatemia.⁸ Our ability to identify patients most likely to suffer harm from hyperglycemia remains incomplete.

Several studies have concluded that the association between hyperglycemia and in-hospital mortality is attenuated among those with preexisting diabetes mellitus, with some even failing to demonstrate any association at all.

Glucose variability (the difference between daily minimum and maximum glucose levels) may be a reflection of dysglycemia induced by severity of illness, inadequate control of glycemia by the treating clinicians resulting in excessive fluctuations of BG levels, or both. Additionally, patients with increased glucose variability are more likely to have experienced hypoglycemia, complicating the assessment of glucose variability versus hypoglycemia and mortality. Over the last several years a plethora of data, from observational studies evaluating a wide variety of acutely and critically ill populations, has confirmed the correlation between glucose variability and increased odds of death. These findings raise the question that attempting to control hyperglycemia may be a major contributing factor in glucose variability and subsequent detrimental outcomes. There has been hope that continuous glucose monitoring will decrease variability and improve outcome, although the one study conducted thus far has failed to show such a relationship.⁹

In summary, it was naïve to conclude after a single center study² that a single intervention (tight glucose control) would lead to an impressive mortality benefit in our complex critically ill patients with organ failures. A single study should never be followed by widespread promotion and adoption of a basic intervention. For an intervention to be adopted, it should be reproducible in a realistic environment, with a clear benefit that outweighs the risks.

The current recommendations for critically ill patients overall, and for patients with severe sepsis, are that insulin therapy should be started when blood glucose exceeds 180 mg/dL with the goal of maintaining blood glucose between 144 and 180 mg/dL with insulin when necessary. However, even this less stringent advice needs to be validated in future studies.