With this study, we explored the association between intravenous insulin and glucose infusion and ICU and hospital mortality. In this mixed population of critically ill patients, the amount of intravenous insulin and glucose infusion was both associated with ICU mortality after correction for confounders. Glucose infusion was not related to hospital mortality. However, based on these results, it is unknown whether this association is an epiphenomenon (since more severely ill patients have more dysglycemia) or represents a true harm from insulin and glucose infusion. Furthermore, age, severity of disease (expressed as maximum SOFA score), hypernatremia and percentage low BG measurements were all associated with mortality, as can be expected. Additionally, we analyzed patients admitted > 72 h, to ensure a cohort of the most seriously ill patients. Results were roughly comparable with the complete cohort of patients admitted > 24 h.
Intravenous insulin was associated with (ICU) mortality with an adjusted OR of 1.06 per 0.1 IU/kg added (95% CI 1.02–1.09). The average insulin use was 0.4 IU/kg/day (IQR 0.2–0.7). The relationship between insulin and mortality was barely affected by adjustment for history of insulin use, severity of disease, low BG measurements and other confounding factors.
Our results are in line with a post hoc analysis of the first Leuven study that showed that the daily insulin dose was a risk factor for ICU mortality (OR 1.060 per 10 IU/day added, 95% CI 1.02–1.09, p = 0.005). Since the ORs for mean BG exceeded those for the insulin dose, the authors concluded that glycemic control was more important than insulin dose in predicting mortality . Only in patients admitted > 24 h, mean BG concentration seems to have a protective effect on mortality risk. Contrary to the limited amount of evidence in critically ill patients, in type 2 diabetes numerous epidemiological studies have showed a (dose-dependent) relation between insulin and adverse events (e.g., cardiovascular events, malignancies and mortality) [32, 42,43,44,45,46]. However, all these types of studies are confounded by reverse causality and confounding, especially by the exposure to other (complex) BG lowering regimens . Mechanistic studies suggested that the insulin resistance of type 2 diabetes leads to a chronic state of compensatory hyperinsulinemia, which induces renal fluid retention, increased sympathetic activity and cell proliferation and differentiation [47, 48]. However, the effects of chronic hyperinsulinemia are unlikely to evoke in critical illness and data on the pathophysiological mechanism in ICU patients are scarce, although it is known that the regular insulin pathways react differently on exogenous insulin [31, 49].
Our results are in contrast to several studies in ICU patients that suggested that insulin infusion has protective effects on apoptosis after myocardial infarction  and induced lowering of inflammation markers , but those studies were not designed to assess clinical outcomes. However, the association between insulin use and mortality will be strongly influenced by the severity of disease, which will result in higher insulin resistance. We tried to correct for this by using both the APACHE IV-predicted mortality score and the maximum SOFA score, which might reflect the occurrence of organ failure during admission. In this study, we found no independent association between glucose variability and mortality, in contrast to previous studies in this and other ICUs. However, theoretically it could be argued that insulin use is one of the patient-related factors that could link glycemic variability to mortality, although there are to our knowledge no studies investigating this pathophysiological link.
The amount of glucose infused was low in this population with a median daily i.v. load of 0 in all patients and 1.3 g per day in patients with a length of stay > 72 h. It is therefore remarkable that after correction for confounders, intravenous glucose infusion was associated with ICU mortality with an OR of 1.01 per g/day increase (95% CI 1.00–1.01). We corrected for hypernatremia, percentage low BG and total parenteral feeding since these are the main indication for intravenous glucose and carry a worse prognosis by themselves. This result is consistent with a retrospective study in 273 long-stay (> 7 days) patients in a Dutch ICU, showing that the amount of infused glucose was independently related to ICU and hospital mortality . In that study, 66 g glucose/day was infused. Moreover, the amount of infused insulin was not different between ICU survivors and non-survivors, but unlike our ICU, insulin therapy was only started above a glucose level of 12 mmol/L at discretion of the attending physician. In the Leuven study, glucose infusion was 200–260 g/day (from admission day 2 onward). Nevertheless, from these studies it remained uncertain whether infusion of exogenous glucose is also harmful when blood glucose is kept in range with the use of insulin. In contrast, several post hoc analyses of recent trials that compared early versus late parenteral nutrition found no association between glucose dose and worse outcome [52, 53].
In this study, we included a mixed cohort of critically ill patients, while it is plausible that there are important differences depending on the underlying illness. By using data from patients who were admitted > 72 h, we excluded the main part of the less severely ill, elective surgery, patients. However, included patients still differ in their nature and severity of disease. In general, more severely ill patients might have higher insulin needs (due to more insulin resistance) and higher glucose needs (due to conditions like liver failure, ileus, etc.). We tried to correct for this, but since this study was retrospective by design, we cannot draw conclusions on causality and the associations that were found can still be an epiphenomenon.
The standard of care in our ICU differs from the local practice in other ICUs. Here, patients do not receive parenteral feeding routinely. Almost all patients received a single dose of dexamethasone (1 mg/kg with a maximum of 100 mg) on admission to the ICU to reduce the systemic inflammatory reaction and to achieve shock reversal as part of the local practice. Glucocorticoids are known to impair insulin-mediated glucose uptake in skeletal muscles . As almost all patients received steroids, we cannot assess their effect on the outcome measures. Continuous renal replacement therapy is carried out with the use of a commercially prepared bicarbonate-buffered hemofiltration replacement solution (HF32bic, Dirinco BV, Oss, the Netherlands). This replacement fluid contains one mmol/l glucose-anhydrate. Glucose can easily cross the membrane and contribute to a positive or negative glucose balance depending on patients’ characteristics [55, 56]. Since targeted BG levels in ICU patients are between 6 and 9 mmol/L, theoretically there will on average be a gradient toward glucose removal. All this together limits generalizability, and results should be interpreted with caution.