Intensive insulin treatment improves forearm blood flow in critically ill patients: a randomized parallel design clinical trial

Stress-induced hyperglycemia is a relatively common condition in patients admitted to intensive care units. It occurs in almost all patients with diabetes, as well as in patients with previously normal glucose metabolism [1]. Hyperglycemia (defined as a fasting plasma glucose >11.0 mmol/l) results from a reaction to a tissue injury or infection [2]. To date, the goal of hyperglycemia treatment has focused on maintaining glucose levels between 8.8 and 11.0 mmol/l. However, in a prospective, randomized, controlled study, it was shown that intensive insulin treatment maintaining glucose levels below 6.1 mmol/l significantly reduces both the mortality and the morbidity in critically ill patients in the surgical intensive care unit [3]. In another study of medical critically ill patients, morbidity but not mortality was reduced by intensive insulin treatment [4].

Recent data, however, indicate that intensive insulin therapy does not have a beneficial effect in critically ill patients and that it increases the risk of serious adverse events related to hypoglycemia; in the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study it was found that intensive glucose control increases mortality among patients treated in the intensive care unit [5, 6]. Therefore, there is no definite answer of whether intensive glucose control has a long-term beneficial effect on the survival of critically ill patients, and the effect of insulin in these patients is not clearly understood. Most likely, insulin has different effects, and, among other factors, these effects are probably due to the improvement of vasodilation in peripheral circulation based on increased activity of the endothelial nitric oxide synthase (eNOS) [7].

The purpose of this study was to investigate if intensive insulin treatment in critically ill ventilated patients causes a change in forearm flow, and what is the relation between the forearm flow and the blood glucose concentration.

The study was conducted on patients admitted to the Department of Intensive Internal Medicine, General Hospital Celje, Slovenia, between January 2005 and December 2006. We included those critically ill patients who met the criteria for severe sepsis with acute respiratory failure requiring artificial ventilation. The following criteria for severe sepsis were considered: body temperature above 38°C or below 36°C, heart rate over 90 bpm, respiratory rate over 20 breaths/min or partial pressure of arterial carbon dioxide below 32 mmHg, leukocyte count over 12.0 × 10⁹/l or below 4.0 × 10⁹/l [8]. Those patients were included who met at least two criteria of sepsis. No diabetic patients were included in the study. Patients requiring artificial ventilation due to primary failure of respiratory muscles and those who required artificial ventilation due to brain injury were also excluded. Prior to inclusion, the patients' legal representatives signed written consent for participation in the study. The patients were randomized into two groups as regards the regulation of blood glucose: intensive (Group 1) and conventional (Group 2). In the conventional protocol the blood glucose concentration was maintained within the range of 7.0 to 11.0 mmol/l, while in the intensive protocol the concentration was maintained within the range of 4.4 to 6.1 mmol/l. The lower level (7 mmol/l) in patients receiving the conventional protocol was selected as per the proposal by the supervisory committee, because the recommendations at that time favoured blood glucose levels less than 8.3 mmol/l [9]. In a 50 ml syringe, 50 IU of human insulin for intravenous administration was diluted in a 0.9% solution of sodium chloride. The amount of infusion was adjusted according to the values of blood glucose concentrations in conformity with a previously published protocol [10]. The blood glucose concentration was determined hourly using the hexokinase method at the beginning of insulin treatment, and every two hours thereafter, except when the dose of insulin was adjusted; in this case, the next measurement was taken after one hour. The treatment was initiated within 48 hours of the start of artificial ventilation. Up to that point, the blood glucose concentrations were maintained in the 8.8 to 11.0 mmol/l range by means of subcutaneous administration of rapid-acting insulin or the infusion described above.

Hypoglycemia, a possible adverse event occurring during insulin treatment, was defined as a decrease in blood glucose concentration to values below 2.2 mmol/l, and was suspected in cases where the patient suffered sudden perspiration, convulsions, and change in heart rate or blood pressure. In these cases, administration of insulin was interrupted and blood was taken to determine the glucose levels. In addition, we performed a bedside test to determine the glucose values. If the blood glucose values were found to be below 2.2 mmol/l, we terminated the insulin infusion and the patient was intravenously administered 25 g of glucose in the form of a 50% solution.

All patients were continuously subjected to hemodynamic monitoring with the following measurements: continuous monitoring of the electrocardiography curve, and invasive measurement of arterial and central venous pressure. Cardiac output was continuously monitored by means of the thermodilution method (Edwards Lifesciences, Vigilance, Irvine, CA, USA).

Any additional monitoring was introduced by the principal physician, depending on the patient's clinical status.

The severity of the patients' clinical status was assessed by means of the Acute Physiology and Chronic Health Evaluation (APACHE) II score system routinely used for all patients treated at the department [11, 12]. All patients were artificially ventilated with a Siemens Servo ventilator 300 set (Danvers, MA, USA) to pressure regulated volume control with a tidal volume of 5 to 7 ml/kg.

The patients were given food using a nasogastric tube as soon as possible, mostly after the initial 12-hour volume resuscitation. The food was administered between 6 a.m. and 10 p.m. During the overnight break in feeding the insulin dose was halved regardless of the insulin treatment protocol. Patients who did not tolerate enteral feeding received food in the form of a parenteral infusion of nutrients, and the insulin dose was adjusted based on the blood glucose levels.

The study was approved by the State Ethics Committee.

To our knowledge, our study was the first to investigate the influence of intensive insulin treatment on forearm flow in critically ill, artificially ventilated patients. We found a significant flow increase 24 and 72 hours after the start of intensive treatment, whereas two hours after the start there was a borderline increase. With respect to the type of treatment, our groups differed only in the quantity of insulin administered to the patients within 24 hours. The initial volume resuscitation was carried out primarily with a crystalloid infusion, while a comparable number of patients also received low doses of hydroxyethyl starch. A recent study showed treatment with this colloid to be inappropriate due to increased incidence of adverse effects on the renal function and coagulation, increased need for blood transfusions, and adverse effects on survival [6]. During the study there were no differences in global hemodynamic parameters or in vasoactive norepinephrine treatment. During our study, no severe hypoglycemia was observed; this fact contrasts with the most recent studies, which have recorded 6.8% to 17% of severe hypoglycemic incidents [5, 6]. The most probable explanation for the absence of hypoglycemia in our study is the relatively small sample of patients and the short period of intensive insulin treatment in comparison to other studies. The flow was in a linear, although weak, interrelationship with the rate of the insulin infusion. Conversely, our study did not confirm the interrelationship between the glucose concentration and forearm flow, which cannot be definitively explained. In another study the influence of intraarterial insulin infusion on protein synthesis in skeletal muscles in the legs was investigated in patients with burns [16]. In addition to the increased utilization of amino acids, they also found that the flow in the legs increased significantly.

The increase of blood flow could be related to the improvement of endothelial function.

The influence of insulin on the endothelial function has been studied extensively and it has been shown that the influence appears through the activation of eNOS [17–19]. The flow in skeletal muscles increases in two phases: first the dilatation of terminal arterioles triggers capillary recruitment within minutes, and in the second phase larger arteries dilate and the flow increases, the effect reaching its peak after two hours [20, 21]. In sepsis, the stimulation of eNOS is inhibited and consequently the response of the endothelium on the insulin is limited [22]. In our study there was a nonsignificant increase in blood flow two hours after the start of the treatment. This could be a result of a delayed response, especially of large arteries, to the insulin infusion.

Our study indicates that insulin treatment improves skeletal muscle blood flow. The weak linear relation between the amount of the infused insulin and forearm flow in our study indicates that the regulation of the flow through skeletal muscles has been preserved and that it may be increased by means of therapeutic procedures such as insulin infusion. This presumption is in agreement with findings of Van den Berghe and colleagues, who showed that intensive insulin treatment significantly reduces the mortality and morbidity of critically ill patients [3, 4]. However, recent data mitigate the positive effects of intensive insulin treatment of critically ill patients or suggest that a goal of normoglycemia does not necessarily benefit critically ill patients and may be harmful (the NICE-SUGAR study) [5]. These findings could mean that increased blood flow in the forearm is not an indicator of improvement of all perfusion (especially vital organs) in critically ill patients, but can be an indicator of the re-distribution of blood flow. The different findings in our study in comparison to the NICE-SUGAR study could also be a consequence of the duration of the follow-up period. In our study, we only followed patients for 72 hours. One possible explanation, thus, is that intensive glucose control has time-limited positive homodynamic effects (up to some days), and that afterward the positive effects of intensive insulin treatment are concealed by a higher complication rate related to adverse events, especially hypoglycemia.

There are some limitations to our study: the sample of patients was relatively small and the study was not completely blind; following randomization, the patients' principal physicians and nursing staff were informed of the type of insulin treatment protocol. During flow measurements, bias was minimised by coding the plethysmographic recordings and independent calculations of flow measurements.

Compared with conventional treatment, the intensive treatment of critically ill patients with insulin results in increased arterial flow in the forearm. An increase in blood flow was indicated in the group of intensively treated patients after two hours, and became significantly greater after 24 hours and 72 hours. The increase of blood flow in the forearm is in a weak linear relationship to the rate of insulin infusion, although no relation with the glucose concentration was found. Based on our findings, it may be concluded that a certain increase in flow may be reached with insulin doses, which do not cause a dramatic reduction in blood glucose values below the acceptable level. Further research is required to determine long-term effects of the increase in blood flow in muscles during intensive insulin treatment of critically ill patients.