In this study, we purposefully selected a well-represented study population of critically ill patients admitted to ICUs from a large critical healthcare database and investigated the clinical outcomes of these patients with and without diabetes, in addition to exploring the impact of blood glucose level at admission on the presence or absence of diabetes. We found that 1) diabetes was not a detrimental factor for critically ill patients in the ICUs, which would reduce the risk of 28-day mortality by about 29%, 2) a V-shaped relationship was observed between blood glucose level and 28-day mortality in patients without diabetes, and hypoglycemia or hyperglycemia should be avoided, especially in patients admitted to the SICU, CSRU, and CCU; for patients with diabetes, no optimal threshold for glucose has been identified, and an elevated blood glucose level does not appear to be associated with a poor prognosis and is perhaps beneficial for certain ICU patients, and 3) particular attention should be paid to hypoglycemic events in critically ill patients without diabetes in the SICU and hyperglycemic events in all critically ill patients in the CCU and CSRU regardless of the presence of diabetes, which warrants the attention of clinicians.
Currently, the mechanisms underlying what appears to be a predominantly neutrally or protective link between diabetes and mortality in critically ill patients continue to be elusive. If diabetes is associated with decreased mortality in patients with critical illness, just a single mechanism may not be involved. Biologically, part of the potential mechanism may be that glucose plays a critical role in the function of activated immune cells and that glucose is a key contributor to energy production and maintenance of immune cell functions as well as the synthesis of immunomodulators [31–33]. Furthermore, diabetic patients develop a tolerance to hyperglycemia because of chronically elevated blood glucose concentrations, making the harmful hyperglycemia transform into an “energy factory” [34], and for the harmful effects to persist, higher blood glucose concentrations would be required [35, 36]. Namely, the smoothing splines revealed graphically that blood glucose level has a relatively small effect on patients with diabetes, and in subsequent further analyses, elevated blood glucose was not statistically associated with an increase in 28-day mortality. Our results also revealed an association between the use of insulin and diabetes on 28-day mortality, that is, there was a significant reduction in 28-day mortality in patients with diabetes who used insulin, whereas no such difference between patients with and without diabetes who did not use insulin was observed. Further analysis of the with or without insulin used cohort revealed that only 1732 patients (11.85%) had diabetes in the non-insulin cohort, which may have weakened the decreasing effect of 28-day mortality in the diabetes cohort and resulted in the negative findings. However, this does not completely refute the association between diabetes and favorable outcomes, from an HR of 0.86 in multivariable analysis to an HR of 0.76 in stratified analysis, suggesting that the insulin use further reduced 28-day mortality in diabetic patients. The underlying mechanisms have been partially explained in previous studies with dysfunctional autophagy in critically ill patients, which plays a key role in both host defense and cell survival [37, 38]; insulin not only plays a role in glucose regulation but also inhibits the autophagic catabolic process [39]. Still, the occurrence of hypoglycemia resulting from the use of insulin should not be ignored. Although the incidence of hypoglycemia was high in the two Leuven studies [4, 5], the condition of patients who experienced hypoglycemia did not worsen when compared to that in who did not experience hypoglycemia. The use of intensive insulin therapy to lower the blood glucose level to normal values requires careful monitoring of blood glucose, as classical neurological symptoms can be offset by sedation or underlying mental status disorders.
In terms of glucose concentrations, glycemic control in critically ill patients is still an area of considerable concern. The initial recognition of the potentially detrimental effects of hyperglycemia prompted a sequence of studies that targeted intensive insulin treatment strategies with the goal of tight glycemic control. With the accumulation of knowledge, however, there have been mixed results regarding interventions for intensive insulin therapy, i.e., the excessive pursuit of tight glycemic control in critically ill patients is exactly a counterproductive step [4–7, 14–19, 40–44]. On the basis of the data from the two Leuven studies, it was considered practical to achieve blood glucose levels of 80-110 mg/dl (rather than 180-200 mg/dl) [4, 5]. The NICE-SUGAR study concluded that a blood glucose target of 180 mg/dl or less was less likely to result in mortality than a target of 81-108 mg/dl [7]. Krinsley et al. adopted different glycemic control strategies on the basis of diabetes status and hemoglobin A1c (HbA1c) levels in critically ill patients and found that a blood glucose level of 80-140 mg/dl was safe and effective in patients without diabetes and in those with diabetes but with a low HbA1c level; however, for patients with diabetes and HbA1c levels greater than 7%, the glycemic target remains ambiguous [19]. These findings mean that the moderate glycemic control strategy has been widely established in critically ill patients. Additionally, the quality of glycemic control can have an impact on clinical outcomes [20, 45]. Glycemic variability has been found to be an independent risk factor for adverse outcomes in critically ill patients [15, 46–48]. Uyttendaele et al. found that the quality of glycemic control in critically ill patients is related prognostically rather than because of the metabolic status [20]. However, the study conducted by Krinsley et al. suggested that diabetes status modulates glycemic control and mortality, as shown by the fact that diabetic patients may benefit from a higher glycemic target range compared to critically ill patients without diabetes [15, 48]. In our opinion, diabetes affects organisms in many aspects, not only resulting in abnormal blood glucose levels but also in the inflammatory response to the disease itself and to factors such as trauma, which can disrupt insulin sensitivity. However, the quality of glycemic control also affects blood glucose levels, with hypoglycemia, hyperglycemia, and glucose variability having deleterious effects on clinical outcomes. Currently, an accurate answer regarding optimal blood glucose concentrations remains elusive. Moreover, the complexity and variability of conducting large samples of clinical trials is well known. Our findings were consistent with the “personalized” treatment strategy for patients with and without diabetes. In our study, for patients without diabetes, the glucose concentration corresponding to the lowest 28-day mortality was 101.75 mg/dl (95% CI 94.64-105.80 mg/dl), whereas for critically ill patients with diabetes, hyperglycemia did not significantly increase the 28-day mortality, and they even benefited from a higher blood glucose level (up to 200 mg/dl), with the exception of patients admitted to the CCU and CSRU. Our study primarily established an optimal threshold for the glycemic range by retrospective analysis of a large sample, which may potentially inform the practice of glycemic control and treatment strategies in critically ill patients. Nevertheless, it should be noted that we used blood glucose concentrations at ICU admission, and we acknowledged that this might not be fully extrapolated to the optimal range of glycemic control.
There are limitations of our study as well. First, we attempted to obtain information on the plasma glucose levels at ICU admission to eliminate the influence of interventions on glucose levels, but we were unable to definitively state whether the interventions that the patients received before ICU admission, such as intravenous fluid administration and steroid hormone injection, affected glucose levels. Second, as no data on HbA1c levels are available yet, we cannot exclude the possibility of new-onset diabetes. Indeed, in previous studies on measuring HbA1c in patients without diabetes, it was found that 5.5%, 6.8%, and 9.3% of critically ill patients had higher than normal HbA1c levels [49–51], confirming that certain patients may have had undetected diabetes before ICU admission. In addition, it should be emphasized that our study did not differentiate the patients' diabetes type (e.g., type 1 or type 2). Third, we were unable to obtain information on the duration, severity, and complications of diabetes, as well as medication prescribed and therefore could not measure the impact of these factors on the outcomes. We used different models, including inverse-probability-weighted analysis, to investigate the independent role of diabetes and the clinical outcomes, but as with all retrospective studies, it was possible that residual confounders may exist. However, these clinical and electronic data were prospectively collected and independently measured, which makes them not easily amenable to manipulation. In addition, with the calculation of E-value to quantify the potential impact of unmeasured confounders, we found that unmeasured confounders are not likely to contribute to the overall effect. Fourth, we should be cautious in interpreting these results, as the results of a correlation analysis should not be mistaken for proof of causality. Finally, as the single-center study design results in reduced external validity, the aspects of glycemic control strategies and mortality reduction differing between critically ill patients with and without diabetes warrant prospective studies that can address the aforementioned limitations.