Hyperglycaemia without diabetes
Hyperglycemia without diabetes is also referred to as ‘stress induced diabetes’. Most likely, patients without diabetes who experience stress induced hyperglycemia are at risk for developing diabetes later in life. Stress induced hyperglycemia was found to be associated with adverse outcome in different cohorts of hospitalized patients. In 2001, van den Berghe et al. reported an impressive reduction in mortality in patients admitted to a surgical intensive care unit (ICU) by treating stress induced hyperglycemia with insulin. Most of these patients did not have diabetes mellitus. Further studies in the same centre showed similar reductions in mortality in medical and pediatric ICU patients. However, the beneficial effects could not be confirmed in a large multinational trial in adult medical and surgical ICU patients. Current guidelines recommend that excessive stress hyperglycemia in hospitalized patients should be treated. The target range for glucose levels should be between 7.8-10 mmol/l, because aiming for a lower glucose range increases the risk for potentially harmful hypoglycaemia.
Tissue damage contributes to the development of hyperglycaemia. Stress hormones, such as adrenaline and noradrenaline, and cytokines, such as interleukin -1 and tumor necrosis factor alpha, are released as a response to tissue damage. This stress response creates a hypermetabolic state in which it seems likely that the amount of tissue damage is related to the degree of hyperglycaemia.
Glucose uptake is increased in insulin independent tissues such as the brain. In tissues dependent on insulin for glucose uptake, stress induced insulin resistance contributes to hyperglycaemia. Many patients with stress induced insulin resistance are likely to have some degree of pre-existent insulin resistance, which attributes to the development of hyperglycaemia: 24-25% of patients without known diabetes but with hyperglycaemia at admission for stroke or myocardial infarction fulfilled the criteria for diabetes, and a further 28-31% met the criteria for impaired glucose tolerance when tested three months after hospitalization.
Stress induced hyperglycaemia in patients without diabetes
Stress induced hyperglycaemia is found in 4-12% of hospitalized patients without known diabetes. An association between stress related hyperglycaemia and adverse outcome was described in various patient groups: patients with myocardial infarction, stroke, cardiovascular surgery, pneumonia, patients who underwent vascular surgery and patients admitted to a general ward. As described above, the amount of tissue damage, or the severity of illness is likely to be related to the degree of hyperglycaemia. It is thus possible that patients with stress induced hyperglycemia are simply sicker patients, and that hyperglycemia itself is not the cause of a worse prognosis.
Evidence for strict glycemic control in patients with stress induced hyperglycemia
Therefore, an important question to be answered was whether lowering stress induced hyperglycaemia would lead to improved outcome. In 2001, in a landmark study, van den Berghe et al. described an absolute mortality reduction of 3.4% in surgical ICU patients, largely without a previous diagnosis of diabetes, when stress induced hyperglycaemia was lowered to 4.4-6.1 mmol/l using intravenous insulin. The conventional arm in this study only received insulin therapy when glucose values exceeded 12 mmol/l. Glucose levels in the conventional arm were then lowered to 10-11 mmol/l.
Subsequent studies in the same centre in Leuven showed that medical ICU patients and pedicatric ICU patients also had a better chance of survival when stress induced hyperglycemia was treated with intensive insulin therapy. A large multicentre, international trial was designed to confirm these findings. In this study, over 6000 patients were randomized to receive either strict glycemic control (glucose target 4.5-6.0 mmol/l) or conventional treatment (glucose target < 10 mmol/l). No difference in survival, length of mechanical ventilation or length of hospital stay was observed.
Also a meta-analysis of 26 trials investigating the use of intensive insulin therapy in patients admitted to an intensive care unit did not show a beneficial effect. Fewer studies were performed investigating the use of intensive insulin therapy in non critically ill patients. A meta analysis of nine randomized studies and ten observational studies also failed to show an important advantage for intensive insulin therapy, except for a small beneficial effect on the occurrence of infections.
It is important to note that the studies compared in the meta-analysis of both ICU and non-ICU patients differed from each other in many aspects, such as reason for hospital admittance, inclusion of patients with known diabetes and target level of glucose control. Also, the target range for glucose control was not always achieved. Especially in a general ward it can be difficult to achieve near normoglycaemia without substantially increasing the risk for hypoglycaemia.
Risk for hypoglycaemia in the treatment of stress induced hyperglycaemia
So, is aggressively lowering stress induced hyperglycaemia potentially harmful? Intensive insulin therapy undoubtedly increases the risk for hypoglycaemia. It has been debated whether hypoglycaemia induced by intensive insulin treatment has adverse effects. It is plausible that the most severely ill patients have a higher risk for hypoglycaemia, and, severity of disease like for hyperglycaemia, is a confounder in the relationship between hypoglycaemia and adverse outcome. When correcting for severity of disease, however, hypoglycaemia that occurs in the setting of intensive insulin therapy does appear to be related to mortality.
Recommendations for the treatment of stress induced hyperglycaemia
Current guidelines recommend that glycaemia is monitored in patients without known diabetes for the first 24-48 hours of hospital admission, and during treatment with glucocorticoid medication, octreotide or when patients receive parenteral or enteral nutrition. Glucose monitoring can be stopped if glucose levels remain <7.8 mmol/l .
Since the risk for hypoglycaemia outweighs the possible beneficial effect of intensive glucose lowering, the suggested target for glucose levels during hospitalization is between 7.8-10 mmol/l. The best way to achieve adequate glucose control in the intensive care unit is by using intravenous insulin administration. The risk for hypoglycaemia can be substantially reduced by using a validated computerized algorithm. For patients admitted to a general ward it is recommended that insulin is used to lower glycemia. Oral glucose lowering agents are less effective, and may be contraindicated in patients with renal failure, liver disease or heart failure. Basal bolus regimens are usually more effective and associated with less hyperglycemia than sliding scale regimens.
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