Glycemic Control in the Critically Ill

Metabolic Response to Critical Illness

Critically ill patients admitted to the ICU with severe injury or infection such as burns, trauma, or sepsis commonly enter into a hypermetabolic state. This state is associated with enhanced peripheral glucose uptake and use, ^[139] hyperlactatemia,^[140] increased glucose production,^[141] depressed glycogenesis, ^[142] and insulin resistance.^[141] Glucose intolerance develops after uptake of glucose in the skeletal muscle, adipose tissue, liver, and heart becomes saturated,^[143] and hyperglycemia occurs because of defective suppression of gluconeogenesis and resistance to the peripheral actions of insulin. These mechanisms all work to generate a hyperglycemic state to satisfy an obligatory requirement for glucose as an energy substrate. The intensity of the metabolic response peaks several days after the initial insult and then diminishes as the patient recovers.^[140] However, a prolonged hyperglycemic response may occur in patients who continue to have tissue hypoperfusion or persistent infection, which then predisposes them to progressive metabolic derangements and multisystem organ failure.

Strict Glycemic Control

Traditionally, hyperglycemia from sepsis was viewed as a beneficial response because it promoted cellular glucose uptake when cells were energy deprived. A glucose concentration of 160 to 200 mg/dL was commonly recommended and was thought to maximize cellular glucose uptake without causing hyperosmolarity.^{[144] [145]}

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Van den Berghe and coworkers^[152] hypothesized that even mild hyperglycemia (i.e., blood glucose level between 110 and 200 mg/dL) could be harmful by predisposing the critically ill patient to increased morbidity and mortality. They performed a prospective, controlled study involving 1548 surgical ICU patients randomized to receive intensive insulin therapy (i.e., blood glucose maintained between 80 and 110 mg/dL) or conventional treatment (i.e., blood glucose maintained between 180 and 200 mg/dL). In patients who remained in the ICU for more than 5 days, intensive insulin therapy reduced the mortality rate from 20.2% with conventional therapy to 10% with intensive therapy (P = .005). The group receiving intensive insulin therapy also had a lower incidence of bloodstream infections (4.2% vs. 7.8%, P = .003), renal failure requiring dialysis (4.8% versus 8.2%, P = .007), and critical illness polyneuropathy (28.7% versus 51.9%, P < .001). Patients in the intensive insulin group were also less likely to require prolonged mechanical ventilation and intensive care. The results of this trial make a persuasive argument for tighter glucose control, at least in surgical ICU patients.

Opponents of the use of strict glycemic control in critically ill patients argue that the risks of hypoglycemia should be seriously considered and that the therapeutic effect of insulin leads to the beneficial outcome, rather than glycemic control. Insulin has multiple effects, including inhibition of tumor necrosis factor-α,^[153] which triggers procoagulant activity, fibrin deposition, and inhibits macrophage inhibitory factor, which contributes to endotoxemia and toxic shock.^[154] To determine whether it was insulin effect or glycemic control, Van den Berghe and colleagues ^[155] used multivariate analysis to reanalyze their prior data. It appeared that lowering of blood glucose levels, rather than the actual amount of insulin given, was most closely correlated with the beneficial reductions in mortality, polyneuropathy, and bloodstream infections. They reported no adverse effects from hypoglycemia in their study. Instead of the glucose level, the dose of insulin was found to correlate with the incidence of renal failure. Investigators ^[156] thought that this difference might result from a direct effect of insulin on the kidney or the need for less exogenous insulin in patients with renal failure because insulin is cleared through the kidney. Finney and associates,^[157] in a prospective, observational study, provided additional evidence that it was glycemic control, rather than insulin administration that provided benefit. They examined the effects of glucose control in 523 patients admitted to a single surgical ICU. In this trial, the primary determinant of a bad outcome was hyperglycemia, rather than hypoinsulinemia, and a lower mortality rate was associated with glycemic control, rather than a protective effect of insulin administration. Increased insulin dosing was associated with an increased mortality rate across all ranges of glycemia. These data suggest that keeping blood glucose below 140 mg/dL may provide similar benefit survival to the "tighter" range of 80 to 110 mg/dL used by van den Berghe and colleagues.^[155]

Based on the van den Berghe^[155] and Finney studies,^[157] it appears that normoglycemia can be safely reached within 24 hours and maintained during the ICU stay. A sample insulin titration order form is provided in Figure 74-2A and Figure 74-2B . Few, if any, clinical trials in the ICU have shown such efficacy. Low tidal volume ventilation lowered relative mortality by 22%,^[9] and treatment of sepsis with APC lowered relative mortality by 20% at 28 days,^[53] but tight glycemic control reduced relative mortality by more than 40%. Unfortunately, the narrow patient population enrolled limits the generalizability of this study. It was limited to those undergoing surgery and therefore cannot be easily extrapolated to other ICUs or patients with other types of critical illness.^[158]