Acute circulatory failure is critical in patients in the ICU. Indices derived from oxygen and CO2 metabolism (CO2-O2-derived indices) including the central venous-to-arterial CO2 difference and central venous-to-arterial CO2 difference/arteriovenous oxygen content ratio are markers for global metabolic demand and tissue hypoxia.

Does a resuscitation strategy using CO2-O2-derived indices improve tissular hypoperfusion compared with standard care?

We conducted a randomized, prospective, multicenter, single-anonymized study in 3 ICUs. Patients aged ≥ 18 years with acute circulatory failure and arterial blood lactate levels ≥ 3 mM were included. Patients were randomized to receive either a CO2-O2-derived algorithm-based treatment or standard clinical practice. The primary outcome was lactate clearance > 10% within 2 hours. Secondary outcomes included Sepsis-Related Organ Failure Assessment score and mortality.

Of the 179 patients enrolled (90 control patients and 89 treatment patients), there was no significant difference in achieving a lactate clearance > 10% at 2 hours between the control (50%) and interventional groups (43.8%) (P = .497). At t2 hours, the median change in lactate levels in the control group was -10.53% (-29.27 to 5.68), whereas in the interventional group, it was -2.70% (-22.58 to 19.1; P = .096). Secondary outcomes did not differ between groups in Sepsis-Related Organ Failure Assessment scores (6 [3 to 9] vs 7 [4 to 10]; P = .719), ICU and hospital length of stay (4.5 days [2.0 to 10.8] vs 5.0 days [2.0 to10.0]; P = .963 and 11 days [3.0 to 27.0] vs 10 days [3.0 to 21.0]; P = .493), or 28-day mortality (44.9% vs 33.3%, P = .150).

Our results indicate that algorithm-based resuscitation using CO2-O2-derived indices did not improve lactate clearance or clinical outcomes compared with standard care. Further research is needed to identify specific patient subgroups who may benefit from this approach.

ClinicalTrials.gov; No.: NCT05032521; URL: www.

gov.

Metformin is the most widely used drug in type 2 diabetes. Regular metformin use has been associated with changes in concentrations of amino acids. In the present study, we used valid stable-isotope labeled GC-MS methods to measure amino acids and metabolites, including creatinine as well as malondialdehyde (MDA), as an oxidative stress biomarker in plasma, urine, and dialysate samples in a patient at admission to the intensive care unit and during renal replacement treatment because of metformin-associated lactic acidosis (MALA, 21 mM lactate, 175 µM metformin). GC-MS revealed lower concentrations of amino acids in plasma, normal concentrations of the nitric oxide (NO) metabolites nitrite and nitrate, and normal concentrations of MDA. Renal tubular reabsorption rates were altered on admission. The patient received renal replacement therapy over 50 to 70 h of normalized plasma amino acid concentrations and their tubular reabsorption, as well as the tubular reabsorption of nitrite and nitrate. This study indicates that GC-MS is a versatile analytical tool to measure different classes of physiological inorganic and organic substances in complex biological samples in clinical settings such as MALA.

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.

Metformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography-mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .