Stress Hyperglycemia in Acute Stroke

Introduction:

Hyperglycemia will be detected in about one third of patients with stroke and can cause detrimental effects of increasing tissue lactic acidosis,secondary to anaerobic glycolysis and free radical production(1). After stroke of either  subtype  (ischemic  or  hemorrhagic),  the unadjusted relative risk of in-hospital or 30-day mortality associated with admission glucose level >6 to 8 mmol/L (108 to 144 mg/dL) was 3.07 (95% CI, 2.50 to 3.79) in nondiabetic patients and 1.30 (95% CI, 0.49 to 3.43) in diabetic patients(2) A good understanding on the pathophysiology and management of stroke hyperglycemia is essential, particularly before one considers administering glucose containing parenteral solutions

Definition of hyperglycemia

The concept of stress-induced hyperglycemia, typically defined as BG concentrations > 200 mg/dl has been described for almost 150 years (3) Various studies assessing   relative risk of 30-day mortality associated with stress hyperglycemia in stroke patients had used a considerable diversity of cut-offs fasting or random glucose levels(2). For practical purpose, in this article hyperglycemia is defined as any BG value > 140 mg/dl or > 7.8 mmol/L (note. 1 mmol/L = 18 mg/dl glucose) (4)

Pathophysiology

The basic mechanism of stress hyperglycemia in acute stroke  is  similar  to  other  acute  illness  or  injury,  ie increase in the concentration of counterregulatory hormones and cytokines(3) . Epinephrine mediates stress

hyperglycemia by altering postreceptor signaling, resulting  in  insulin  resistance.  Epinephrine  also increases gluconeogenesis and suppresses insulin secretion. In addition to hyperglycemia, another effect of epinephrine is hypokalemia (via intracellular shift). Glucagon increases gluconeogenesis and hepatic glycogenolysis. Glucocorticoids and various cytokines also considerably contributes to stress hyperglycemia.

Epinephrine	skeletal  muscle  insulin  resistance  via  altered postreceptor signaling
	increased gluconeogenesis
	increased      skeletal      muscle      and      hepatic glycogenolysis
	increased lipolysis; increased free fatty acids
	direct suppression of insulin secretion
Glucagon	increased gluconeogenesis
	increased hepatic glycogenolysis
Glucocorticoids	skeletal muscle insulin resistance
	increased lipolysis
	increased gluconeogenesis
Growth hormone	skeletal muscle insulin resistance
	increased lipolysis
	increased gluconeogenesis
Norepinephrine	increased lipolysis
	increased            gluconeogenesis;             marked hyperglycemia only at high concentrations
Tumor necrosis factor	skeletal  muscle  insulin  resistance  via  altered postreceptor signaling
	hepatic insulin resistance

Why does glucose, the main energy substrate for the brain, cause damage of brain tissue at the time of cerebral ischemia ?

Shortly  after  being  deprived  of  oxygen,  metabolism within penumbral tissue changes from aerobic to anaerobic glycolysis which is less energy efficient and produces lactate and unbuffered hydrogen ions. Experimental models have consistently shown that animals  made  hyperglycemic  before  induction  of ischemia have higher levels of lactate than euglycemic controls.Hyperglycemia may initially be neuroprotective, with  increased  glucose  available  for  metabolism  and ATP production. Persisting anaerobic metabolism results in the development of intracellular acidosis. It has been shown using both pH-sensitive microelectrodes and 31P nuclear magnetic resonance spectroscopy that the brain pH of animals pretreated with glucose is considerably more acidotic than saline treated controls. Acidosis may exacerbate penumbral injury through enhancement of free radical formation, activation of pH dependent endonucleases, and glutamate release with subsequent alteration of intracellular Ca++ regulation and mitochondrial failure.

There is currently no direct proof that lactate is detrimental to the ischemic brain. In vitro work using murine hippocampal slices has shown that glucose and acidosis are detrimental to cells whereas lactate is not. Using PET scanning it has been shown that lactate may be the preferred energy supply to the brain especially during times of stress. This is relevant to the management of hyperglycemia in acute ischemic stroke patients. If the ischemic brain is dependent on lactate for its source of energy, targeted euglycemia may result in less glucose load to the brain and thus less substrate for anaerobic metabolism, therefore attenuated lactate production. (5)

Summary of Evidence Supporting a Detrimental Role for

Elevated Glucose in Stroke (3,5,6)

1. Experimental ischemic damage is worsened by hyperglycemia.

2. Experimental ischemic damage is reduced by glucose reduction.

3. Early hyperglycemia is associated with clinical infarct progression in brain imaging.

4. Early hyperglycemia is associated with hemorrhagic conversion in stroke.

5. Early hyperglycemia is associated with poor clinical outcome.

6. Early hyperglycemia may reduce the benefit from recanalization.

7. Immediate insulin therapy reported beneficial in acute myocardial infarction and surgical critical illness.

So what?

There is strong rationale to treat stress hyperglycemia in acute stroke. Should we extrapolate the results of randomized clinical trials on glucose control in critically ill patients ?

Randomized clinical trials on glucose control in critically ill patients were first reported in 1995. These studies were done at a time when physicians did not place a high priority on glucose control in hospitalized patients. Physicians used a sliding scale to calculate insulin doses (the true purpose of the sliding scale is not to control glucose but to provide a contingency plan for insulin dosing so that nurses could decide the dose without needing to call the physician, which the sliding scale does admirably). Patients in the ICU with blood glucose concentrations over 11.1 mmol/L (200 mg/dL) were common (7) The DIGAMI (Diabetes Insulin-Glucose in Acute Myocardial Infarction) study was the first clinical trial of tight glucose control in the hospital. This randomized study compared intravenous insulin followed by multiple-dose insulin therapy versus standard care for patients with diabetes and acute myocardial infarction (8)

. Although the authors did not define their protocol, attentive control of blood glucose from the time of admission to the postdischarge period reduced mortality at 1 year by 26%. In 2001, a Belgian group performed the first large randomized trial of tight glucose control in critically ill patients in a surgical intensive care unit. Most patients were recovering from coronary artery bypass surgery (9)  . The authors enrolled anyone with elevated glucose concentrations, not just patients with diabetes. Tight control dramatically reduced the mortality rate from 8% in the control group (in which the glucose control target was 10.0 mmol/L [<180 mg/dL]) to 4.6% in the normal glucose-control group (in which the glucose control target was 6.1 mmol/L [<110 mg/L]). Of note, the glucose control targets for all patients—diabetic or nondiabetic—were those typically set for nondiabetic patients. Although most diabetologists believed that tight glucose control would help, they were surprised by magnitude of the benefit. At that point, the pendulum was at its apogee on the side of tight glucose control, and  major  organizations  issued  guidelines  endorsing tight glucose control in the ICU.

However, when the Belgian group applied their glucose- control protocol to medical ICU patients, the results were very different. The mortality rate in the tight control group was lower in patients who stayed in the ICU for 3 or more days but higher in those who stayed in the ICU less than 3 days (10) . Furthermore, the benefit was much smaller than that seen in the Belgian group's study of patients in the surgical ICU: a 6% reduction in mortality in patients with longer stays in the ICU rather than the 42% reduction seen in the surgical ICU. However In subsequent studies, including the NICE-SUGAR (the Normoglycemia in  Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation)— strongly discouraged against tight glucose control. (11)

Past and Present Attitude

In 2004 active lowering of elevated blood glucose by rapidly acting insulin is recommended in most published guidelines,  even  in  nondiabetic  patients (European Stroke Initiative [EUSI] guidelines >10 mmol/L, American Stroke Association [ASA] guidelines >300 mg/dL) (6) However,  current  evidence  indicates  that  persistent hyperglycemia (>140 mg/dl) during the  first 24  hours after stroke is associated with poor outcomes, and thus it is generally agreed that hyperglycemia should be treated in  patients with  acute ischemic stroke. The  minimum threshold describe in previous statements likely was too high. Therefore a lower serum glucose concentration (possible  >140  to  185  mg/dl)  should  trigger administration of insulin (Class Iia, Level of Evidence C) (12)

Conclusion

Stress hyperglycemia is common after acute stroke and may be caused by the increased release of counterregulatory hormones, such as epinephrine, glucagon and glucocorticoid.

Current recommendation should be followed regarding the treatment of stress hyperglycemia in patient with acute  stroke,  in  view  of  the  grieve  consequences to short-term mortality and poor functional recovery.

Very good understanding in handling stroke hyperglycemia is important before  considering the administeration of  parenteral maintenance fluid therapy containing   glucose,   in   order   to   ensure   functional recovery and avoid complications.

References

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