We found that intensive glucose control did not reduce the morbidity or the mortality of patients admitted to a mixed medical/surgical ICU with medical problems, non-cardiovascular surgeries or trauma. These results differ from two previous studies. The first one with patients in a cardiovascular-surgical ICU [5
] demonstrated a decrease in morbidity and mortality. The other in patients in a medical ICU demonstrated a decrease in morbidity; however, a decrease in mortality was only seen in a subgroup of patients with an ICU stay longer than two days [6
A possible explanation for these differences could be the different type of patients in each study. The first study was conducted in a surgical ICU where 63% of the patients had cardiovascular problems. In these patients, the decrease in mortality recorded for the intensive insulin group was associated with a decrease in both the frequency of infections (46%) and in the number of deaths due to multiple organ failure of known sepsis origin [5
]. In contrast, our study was conducted in a mixed medical/surgical ICU where the patients were admitted with medical problems, non-cardiovascular surgeries or trauma, and where established infection was a common reason for admission (33%). In addition, the intervention did not significantly decrease the rate of ICU-acquired infections (33.2% in the intensive insulin group compared with 27.17% in the standard insulin group). These findings suggest that prevention of nosocomial infections, more than control of established ones, could be a major mechanism for the mortality reduction in patients treated with strict glucose control. Furthermore, the recently finished Volume Substitution and Insulin Therapy in Severe Sepsis trial, a randomised multicentre trial designed to assess the efficacy and safety of intensive insulin therapy in patients with severe sepsis and septic shock, was stopped early for safety reasons [16
]. Of the 537 evaluated patients there was no significant difference between the two groups in the 28-day mortality rate or the mean organ failure score. The rate of severe hypoglycaemia, however, was higher in the intensive insulin therapy group compared with the standard insulin therapy group (17.0% vs. 4.1%, p < 0.001).
The patients in our study were younger (47 years old) than in other studies (63 years old) [5
], and on admission to the ICU the mean APACHE II score was lower in our study compared with the medical ICU study by Van den Berghe and colleagues (15 vs. 23) [6
]. In addition, our population was relatively healthy before the acute process that indicated ICU admission, as less than 14% of them had a significant concomitant disease before admission. Thus, our study population may not be critically ill enough to obtain a benefit from intensive insulin therapy.
The patients in the intensive group in our study did not reach the normal glucose level because our protocols were carefully designed to avoid a high rate of hypoglycaemia. Therefore, this strict control against hypoglycaemia could also become a measure favouring the balance in glucose goals between the groups. Furthermore, the mean values for glucose level in the standard group were lower than expected because our patients did not routinely receive a 10% dextrose infusion, and a lower amount of parenteral calories was supplied from the beginning. Thus, the median difference in glucose values between groups was about 30 mg/dl and although this difference was statistically significant, there was a considerable overlap between the two study groups (Figure ). Such a relatively small effect over glucose control could be one of the reasons no differences were seen in morbidity or mortality rates.
In addition, we observed a large variability of blood glucose concentration in both groups, which has been suggested as another possible explanation for the lack of beneficial effects of insulin therapy [17
]. The delay in the recruitment, much longer than the studies by Van den Berghe and colleagues [5
], may explain our findings as it is possible that any benefit may only be accrued early on.
Severe hypoglycaemia of 40 mg/dl or less was associated with the application of insulin in our setting, as well as in the cardiovascular surgical ICU study [5
], but less frequent than in the medical ICU study [6
]. Hypoglycaemia of 60 mg/dl or less was also more frequently associated with the utilisation of insulin in the intensive group 66% compared with 10% in the conventional group.
There were some limitations in our research. These were related to sample size, which was underpowered to detect both overall differences and those within subgroups. At the time when we planned and conducted our study the only available information about efficacy was inferred from the first trial by Van Den Berghe and colleagues [5
], which showed a 42.5% relative risk reduction over a mortality rate in the control group of about 8%. Based on these data, we assumed the same relative risk reduction but over a higher expected mortality in the control group (i.e. 25%). Therefore, our study is not large enough to say that there was no benefit in the overall population or in the subgroups of medical or trauma/surgery patients. On the other hand, the inability to maintain the blinding because the titration of insulin required monitoring of glucose levels may be a potential source of bias. In order to decrease this problem, those physicians evaluating ICU-acquired infections were blinded to the study group. Finally, this study was performed in only one centre, an obvious constraint to generalise our results.