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Maintain Adequate Glycemic Control

Maintain Adequate Glycemic Control

Corresponding Bundle Element

Glucose control maintained > lower limit of normal, but < 150 mg/dL (8.3 mmol/L).

Related Measures

Glycemic Control Goal

Background

Following initial stabilization of patients with severe sepsis, blood glucose should be maintained < 150 mg/dL (8.3 mmol/L). Studies supporting the role of glycemic control have used continuous infusion of insulin and glucose. With this protocol, glucose should be monitored frequently after initiation of the protocol (every 30–60 minutes) and on a regular basis (every 4 hours) once the blood glucose concentration has stabilized.

Hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in intensive care unit (ICU) patients. It can be considered an adaptive response, providing glucose for the brain, red cells, and wound healing, and is generally only treated when blood glucose increases to > 215 mg/dL (>12 mmol/L). Conventional wisdom in the ICU has been that hyperglycemia is beneficial and that hypoglycemia is dangerous and should be avoided.  This concept has been challenged recently, and controlling blood glucose levels by intensive insulin therapy decreased mortality and morbidity in surgical critically ill patients.

Van den Berghe et al

Van den Berghe et al. [1] recently demonstrated that controlling blood glucose levels by intensive insulin therapy dramatically decreased mortality and morbidity in critically ill patients.  The trial was a large single-center study of postoperative surgical patients.  The design employed a continuous infusion of insulin to maintain glucose between 80 and 110 mg/dL (4.4–6.1 mmol/L). Exogenous glucose was begun simultaneously with insulin with frequent monitoring of glucose (every 1 hour) and intensity of monitoring was greatest at the time of initiation of insulin. 

This protocol was provided by the investigators as an appendix and can be found on the website of the New England Journal of Medicine. In brief, this proceeding leads to a strategy of maintaining normoglycemia with insulin (0.04 units·kg-1·hour-1) during normal intake of glucose (9 g/hr) and normal intake of calories (19 kcal·kg-1·day-1).

Benefits of Intensive Insulin Therapy:

A total of 35 of 765 patients (4.6 percent) in the intensive insulin group died in the ICU in Van den Berghe et al., compared with 63 patients (8.0 percent) in the conventional therapy group.

Intensive insulin therapy halved the prevalence of:

  • Blood stream infections
  • Prolonged inflammation
  • ARF requiring dialysis or hemofiltration
  • Critical illness polyneuropathy
  • Transfusion requirements

Patients receiving intensive insulin therapy were also less likely to require prolonged mechanical ventilation and intensive care.  

Rigorous insulin treatment reduced the number of deaths from multiple-organ failure with sepsis, regardless of whether there was a history of diabetes or hyperglycemia.

Surgical vs Medical Patients

In medical septic patients, such a tight control of glycemia targeted to obtain normal blood glucose levels has not been adequately studied.  However, there is no reason to believe that this strategy is not applicable to medical septic patients. Because medical patients tend to stay in the ICU longer than surgical patients, we suspect that the results from such a study will indicate that this intervention is even more favorable in medical ICU patients.

Hypoglycemia

For septic medical patients, we recommend clinicians pay particular attention to glycemic control to prevent metabolic complications and to ensure adequate nutritional support.  Hypoglycemia may occur when coordinating tight glycemic control.  Post hoc data analysis of the Van de Berghe et al. data revealed that although best results were obtained when glucose was maintained between 80 and 110 mg/dL (4.4 and 6.1 mmol/L), achieving a goal of < 150 mg/dL (8.3 mmol/L) also improved outcome when compared with higher concentrations. This goal will likely reduce the risk of hypoglycemia.

The glucose control may be better if appropriate safety controls can also be put in place.  Implementing tight glycemic control can be dangerous without adequate staff education and a written, explicit protocol, which may help to prevent episodes of hypoglycemia.

Nutritional Support

In patients with severe sepsis, a strategy of glycemic control should include a nutrition protocol with the preferential use of the enteral route.  Initiating glycemic control without adequate provision of calories and carbohydrates will increase the risk of hypoglycemia.  This strategy of strict glycemic control should be carefully coordinated with the level of nutritional support and metabolic status, which changes frequently in septic patients. 

Insulin Delivery vs Normoglycemia

It remains an open question whether the benefits are brought about directly by the infused insulin per se or by the prevention of hyperglycemia, as both occurred concomitantly.

Insulin has been shown to inhibit tumor necrosis factor-a [2]; it is also likely that the infusion of glucose and insulin inhibits macrophage inhibitory factor. [3]  The improved outcomes observed in the group receiving intensive insulin therapy may have resulted primarily from the action of insulin on these cytokines rather than from the relatively mild hyperglycemia in the conventionally treatment group. Besides these anti-inflammatory effects [4], favorable effects on coagulation and fibrinolysis [5,6] and on macrophage function [7], partially mediated by the prevention of hyperglycemia, may also have occurred.  All these effects of insulin could also contribute to the well-documented benefits of treating hyperglycemia to reduce infection.

To answer this question, Van den Berghe et al. [8] analyzed the data in the following way. Multivariate logistic regression analysis revealed that the daily dose of insulin and the mean blood glucose level were independent positive predictors of mortality in the study population.  Metabolic control, as reflected by normoglycemia rather than the infused insulin dose per se, was related to the beneficial effects of intensive insulin therapy. They found that it was a low level of blood glucose, rather than a high insulin dose, that apparently protected against most ICU complications and death, without an identifiable glycemia threshold, below which no further risk reduction occurred.

In summary, a high dose of insulin was associated with a worse outcome, and a lower blood glucose level was associated with a better outcome, suggesting that the latter had a crucial role.

References

  1. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. New England Journal of Medicine. 2001;345:1359–1367.
  2. Satomi N, Sakurai A, Haranaka K. Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: Role of glucose, insulin, and macrophages. Journal of the National Cancer Institute. 1985;74:1255–1260.
  3. Das UN. Is insulin an antiinflammatory molecule? Nutrition. 2001;17:409–413.
  4. Hansen TK, Thiel S, Wouters PJ, et al. Intensive insulin therapy exerts anti-inflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. Journal of Clinical Endocrinology and Metabolism. 2003;88:1082–1088.
  5. Carr ME. Diabetes mellitus: A hypercoagulable state. Journal of Diabetes and its Complications. 2001;15:44–54.
  6. Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor kappa-B and stimulates I-kappa-B in mononuclear cells in obese subjects: Evidence for an anti-inflammatory effect? Journal of Clinical Endocrinology and Metabolism. 2001;86:3257–3265.
  7. Kwoun MO, Ling PR, Lydon E, et al. Immunologic effects of acute hyperglycemia in nondiabetic rats. JPEN. Journal of Parenteral and Enteral Nutrition. 1997;21:91–95.
  8. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Critical Care Medicine. 2003;31:359–366.

Content adapted extensively from:

  • Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Guidelines for management of severe sepsis and septic shock. Critical Care Medicine. 2004;32:858-873.
  • Cariou A, Vinsonneau C,  Dhainaut JF. Adjunctive therapies in sepsis: An evidence-based review. Critical Care Medicine. 2004;32(Suppl.):S562–S570.

Tips

  1. Create a standardized protocol that provides for continuous intravenous insulin infusion and nutritional support for cases of severe sepsis and septic shock .
  2. Allow the protocol to be automatically adjusted by the nursing staff to safely accomplish tight glucose control with a reliable bedside presence. 
  3. Administer glucose or enteral feedings while the insulin infusion is active, with frequent glucose monitoring by finger stick.
  4. Adopt a specific treatment plan for hypoglycemia.
  5. Educate the nursing staff about the benefits of tight glucose control and relieve the fear of increasing the incidence of hypoglycemia. Tight glycemic control in patients can be so foreign to routine clinical practice that fear can defeat the success of the project.
  6. Work closely with nursing in creating the protocols to make sure the increased burden of frequent glucose checks can be integrated into their workflow.