What do we know about micronutrients in critically ill patients? A narrative review

Abstract

Micronutrient (MN) status alterations (both depletion and deficiency) are associated with several complications and worse outcomes in critically ill patients. On the other side of the spectrum, improving MN status has been shown to be a potential co-adjuvant therapy. This review aims to collect existing data to better guide research in the critical care setting. This narrative review was conducted by the European Society of Intensive Care Medicine Feeding, Rehabilitation, Endocrinology, and Metabolism MN group. The primary objective was to identify studies focusing on individual MNs in critically ill patients, selecting the MNs that appear to be most relevant and most frequently investigated in the last decade: A, B₁, B₂, B₃, B₆, folate, C, D, E, copper, iron, selenium, zinc, and carnitine. Given the limited number of interventional studies for most MNs, observational studies were included. For each selected MN, the review summarizes the main form and functions, special needs and risk factors, optimal treatment strategies, pharmacological dosing, and clinical implications all specific to critically ill patients. A rigorous rebalancing of research strategies and priorities is needed to improve clinical practice. An important finding is that high-dose monotherapy of MNs is not recommended. Basal daily needs must be provided, with higher doses in diseases with known higher needs, and identified deficiencies treated. Finally, the review provides a list of ongoing trials on MNs in critically ill patients and identifies a priority list of future research topics.

Keywords: critical illness; inflammation; micronutrients; nutrition; oxidative stress.

Figure 1

Pathways of NAD+ synthesis. There are three different pathways to ensure adequate levels of NAD+. The principal is under control QPRT, a rate‐limiting enzyme in the NAD+ synthesis from tryptophan and is highly expressed in kidneys. It can become downregulated in a stressed kidney. The two others are salvage pathways ensuring some redundance. NAD+, nicotinamide adenine dinucleotide; QPRT, quinolinate phosphoribosyltransferase. Adapted with permission from Koekkoek KWA, Berger MM. An update on essential micronutrients in critical illness. Curr Opin Crit Care. 2023;29(4):315‐329.

Figure 2

Treatment algorithm for copper deficiency or excess: Factors to consider are a depletion mechanism, the acute‐phase response reflected by CRP, and ceruloplasmin. Low ceruloplasmin (<20 mg/L) orients the therapy: IV or oral repletion dose will be determined by the severity and presence or absence of clinical symptoms. Routine screening refers to home enteral nutrition or parenteral nutrition and bariatric surgery every 6–12 months. CRP, C‐reactive protein; IV, intravenous. Reproduced with permission from Altarelli M, Ben‐Hamouda N, Schneider A, Berger MM. Copper deficiency: causes, manifestations, and treatment. Nutr Clin Pract. 2019;34(4):504‐513.

Figure 3

Dual selenite action (quantum selenium biochemistry). Red indicates an oxidant molecule or activated structure or cell; blue indicates an antioxidant; and green indicates protected structures. At concentrations above the toxicity threshold (see lower left quadrant), selenite (Na₂SeO₃) induces redox cycles producing oxidative damages in almost all vital structures including DNA. The more the cells are activated, the greater the penetration of selenite and the corresponding damage. At concentrations below the toxicity threshold, selenium (Se) from Na₂SeO₃ can be incorporated into selenocysteine (SeC) in the last step of Se metabolism. Its metabolism (metabol.) is complex, most probably because of the oxidative toxicity of SeC. It is genetically controlled and energy consuming. Sec is required at the active site of vital antioxidant (antiox.) selenoenzymes. In plasma, SELENOP has a dual function: (1) in oxidative stress: antioxidant enzyme, notably against peroxynitrite (ONOO‐), protecting ESL and endothelial cells; (2) in healthy conditions: transport of SeC from the liver to the tissues where it is delivered (deliv.) and metabolized again. In the acute phase of sepsis, liver SELENOP synthesis and secretion has been observed as strongly downregulated and nonspecific binding increase leading to markedly concentration decrease. GPX‐3 may protect the basal membrane. It is synthetized by the kidney, normally thanks to SELENOP. During sepsis, because of protein catabolism, there is a release of selenomethionine (reserve pool of Se without biological action). Liver content is about 30% of TBSe, and muscle is about 40% in a reserve form (Se‐Met). GPX‐3, plasma glutathione peroxidase; ESL, endothelium surface layer; SELENOP, selenoprotein‐P; Se‐Met, selenomethionine; TBSe, total body Se content. Adapted with permission from Forceville X, Van Antwerpen P, Annane D, Vincent JL. Selenocompounds and sepsis‐redox bypass hypothesis: part B‐selenocompounds in the management of early sepsis. Antioxid Redox Signal. 2022;37(13‐15):998‐1029.

Figure 4

Regulatory mechanisms that affect zinc bioavailability.

Figure 5

The carnitine system. CPTS, carnitine palmitoyl transferase system. This figure is created by the authors of this article but is, with permission, partially based on Foster.