Stress hyperglycaemia and arginine metabolomics in critical illness

Author: Tien Lee

  • Thesis download: available for open access on 8 Sep 2023.

Lee, Tien, 2021 Stress hyperglycaemia and arginine metabolomics in critical illness, Flinders University, College of Medicine and Public Health

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Hyperglycaemia in hospitalized patients, including those with an acute myocardial infarction (AMI) or critical illness, is associated with increased mortality. However, previous studies have reported that the acute rise in blood glucose concentration in hospital, termed stress or relative hyperglycaemia, is more strongly associated with mortality than the absolute glucose concentration (absolute glycaemia). The aim of this PhD project was to investigate whether relative hyperglycaemia is associated with mortality during AMI and critical illness and whether differences in arginine metabolites mediate the relationship between acute hyperglycaemia and mortality.

For AMI, I conducted a post-hoc analysis of data from The Hyperglycaemia: Intensive Insulin Infusion in Infarction (HI-5) study. For critical illness, 1,262 consecutively admitted patients to the Intensive Care Unit (ICU) at Flinders Medical Centre were studied prospectively. Relative hyperglycaemia was defined by the stress hyperglycaemia ratio (SHR), calculated by dividing a patient’s admission glucose concentration by their estimated average glucose over the prior 3 months derived from glycosylated haemoglobin. Arginine and related metabolites have been associated with outcomes in critical care, and may provide a putative link for the effects of stress hyperglycaemia in this cohort. To study this, asymmetric dimethyl-L-arginine (ADMA) and L-homoarginine were measured by liquid chromatography mass spectrometry. An in vitro study was conducted to determine whether hyperglycaemia modulates the activity of dimethylarginine dimethylaminohydrolase-1 (DDAH1), the key enzyme that metabolises ADMA.

In the HI-5 study, SHR, but not absolute glucose, was positively associated with mortality, heart failure, arrhythmia, cardiogenic shock and a composite endpoint of a complicated AMI. These positive findings were not affected by diabetes status. These results show that relative hyperglycaemia is associated with mortality in patients with AMI across the glycaemic spectrum.

In critical illness, SHR was significantly associated with mortality after adjustment for the risk of death score, while the association with glucose was not statistically significant. The relationship between SHR and mortality was similar in patients with and without background hyperglycaemia. The results demonstrate that the relationship between relative hyperglycaemia and mortality is independent of known prognostic markers in ICU patients.

In this cohort of critically ill patients, ADMA was positively and L-homoarginine was negatively associated with mortality, independent of the risk of death score. The addition of ADMA and L-homoarginine significantly increased the area under the Receiver Operator Characteristic curve for mortality, compared to the risk of death score alone. These results suggest that measurement of ADMA and L-homoarginine may refine current models to predict mortality in ICU.

In critically ill patients there was not a significant correlation between ADMA and SHR. Consistent with this, in vitro DDAH1 activity was not affected by acute hyperglycaemia. L-homoarginine was significantly positively associated with mortality, but it is a negative predictor of mortality in this cohort. Therefore, changes in ADMA and L-homoarginine do not underlie the relationship between relative hyperglycaemia and mortality.

In summary, relative but not absolute hyperglycaemia is associated with mortality in AMI and critical illness. This association is not affected by background glycaemia and is independent of other prognostic factors. ADMA and L-homoarginine are also independently associated with mortality in critical illness. However, the relationships between relative hyperglycaemia and endothelial dysfunction and mortality are not mediated via these arginine metabolites.

Keywords: stress hyperglycaemia, hyperglycaemia, arginine, monomethylarginine, asymmetric dimethylarginine, symmetric dimethylarginine, dimethylaminohydrolase, homoarginine, acute myocardial infarction, critical care, critical illness, intensive care, mortality

Subject: Public Health thesis

Thesis type: Doctor of Philosophy
Completed: 2021
School: College of Medicine and Public Health
Supervisor: Assoc Prof Morton Burt