SIRM-study: Using stable isotopes for repeated measurements of glucose, lipid and protein metabolism within a limited time frame

In 2001, a landmark study was published showing an improved outcome in
morbidity and mortality of critically ill patients in the ICU treated with
intensive insulin therapy to achieve euglycemia. The underlying mechanism for
this improved survival has not been clarified yet: either normoglycemia itself
or the metabolic effects of insulin may be responsible (Van den Berghe G,
Wouters P, Weekers F et al. Intensive insulin therapy in the critically ill
patients. N Engl J Med 2001; 345(19):1359-1367).

In an upcoming study that will be performed in the *Onze Lieve Vrouwziekenhuis*
Aalst, Belgium (under supervision of Dr. F. Nobels and Dr. L. Foubert) in
collaboration with the metabolic research group of the Academic Medical Center
in Amsterdam (Prof. Dr. H.P. Sauerwein, Dr. M.J.M. Serlie), we will investigate
this question, by studying glucose, lipid and protein metabolism in male
Caucasian non-diabetic patients undergoing CABG surgery.

In the main study, patients will be randomized to group A or B:
A = low-dose insulin infusion combined with euglycemia starting
intraoperatively and continuing until the first 12 hrs in the ICU
B = high-dose insulin infusion combined with euglycemia starting
intraoperatively and continuing until the first 12 hrs in the ICU
Glucose, lipid and protein metabolism will be measured using stable isotopes on
two occasions: 24 hours before and 24 hours after surgery.

The study design assumes that glucose, lipid and protein metabolism can be
measured twice in a 48 hour interval. In other words, it assumes that the
stable isotopes used to measure metabolism on day 1 do not interfere with the
measurements on day 3.

To verify whether this assumption is correct, we have designed a pilot study,
which is described below.

To determine whether glucose, lipid and protein metabolism can be accurately
measured using stable isotopes in the same patient on two occasions in a 48
hour interval.

Non-randomized intervention study in which each volunteer serves as his own
control.

Each volunteer undergoes identical interventions on day 1 and 3:
- At T = 0h, a primed continuous infusion of all isotope tracers will be
started.
- At T = 2h, an infusion of insulin (20mU/m2*min) and glucose 20% will be
started to maintain a plasma glucose level of 5 mmol/liter (hyperinsulinemic
euglycemic clamp). Blood samples will be drawn regularly to determine the
plasma glucose level.
- At T = 4:30h, the insulin infusion will be increased to 60mU/m2*min.
- At T = 7h, all infusions will be stopped and subjects will be offered a
carbohydrate-rich meal.

Burden: Total in-hospital presence of 18 hours.
Risks: Stable isotopes are not radioactive and act as the normal biological
equivalent and are thereby harmless.
During a hyperinsulinemic euglycemic clamp it is theoretically possible to
induce a hypoglycemia. However, this is very unlikely as blood glucose is
checked every five minutes and the glucose infusion is adapted accordingly.