There are at least two possible explanations for the association between hypoglycemia and outcome. First, the severity of hypoglycemia may be associated with the severity of illness and therefore increased risk of death.42 Second, hypoglycemia might have a true deleterious biologic effect in critically ill patients. For example, hypoglycemic episodes might have biologic toxicity by increasing the systemic inflammatory response,43 inducing neuroglycopenia,44 inhibiting the corticosteroid response to stress,45 impairing sympathetic nervous system responsiveness,46 or causing cerebral vasodilatation,47 or by means of other as-yet-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.45-48 In addition, recent hypoglycemia can reduce autonomic responses and defenses against subsequent hypoglycemia. Whether these mechanisms played a role in the results of the NICE-SUGAR or other trials is currently unclear, but the available data suggest that avoiding even mild hypoglycemia is advisable.49 Some of the patient groups at risk of hypoglycemia have been identified: These include patients with diabetes mellitus (DM), septic shock, and renal insufficiency, particularly patients treated with continuous renal replacement therapy; those being treated with mechanical ventilation and inotropic agents; those with higher severity of illness; and those being treated with IIT.50-52 Although these risk factors have been identified, all critically ill patients being treated with insulin should be considered at risk of hypoglycemia and monitored accordingly.