March 2025 Issue

Micronutrients in the ICU
By Jennifer Doley, MBA, RD, CNSC, FAND
Today’s Dietitian
Vol. 27 No. 3 P. 16

The Current Status of Research

Vitamins and minerals, generally referred to as micronutrients, have numerous functions. Many are enzymatic cofactors in multiple metabolic processes necessary for energy utilization, cell differentiation, immune function, and blood clotting. Others play a role in bone health, vision, neurological function, and fluid balance. Some are also anti-inflammatory or antioxidant compounds.1,2

Risk for micronutrient deficiencies increases with certain diseases and medical conditions. Many patients in the ICU are faced with acute, severe illness characterized by significant inflammation and other metabolic changes. Critically ill patients are more prone to malnutrition, which is often accompanied by micronutrient deficiencies. It is important to assess the ICU patient’s micronutrient status and risk for deficiency, as well as implement treatments when appropriate.

Assessing Micronutrient Status
Micronutrient status is often described in three stages—adequate, depleted, and deficient. Depletion is generally defined as reduced intake or increased losses without the presence of clinical symptoms. Micronutrient deficiency is reduced intake or increased losses, plus clinical symptoms or blood/serum concentrations below recommended ranges.2,3

Assessing micronutrient status in any patient, but especially critically ill patients, can be challenging. Biomarkers are influenced by inflammation and many disease states and are often unreliable indicators of the body’s true micronutrient reserves. The RD should not rely only on lab values when assessing micronutrient status but also consider several other factors.2

The Role of Inflammation
Inflammation is a natural immunologic response to infection, trauma, surgery, and other medical conditions, and its purpose is to initiate the healing process. To maintain homeostasis, anti-inflammatory processes are also activated. However, severe or prolonged inflammation can overwhelm these natural anti-inflammatory responses, potentially causing organ damage and poorer health outcomes for patients with severe inflammation.1,2

Micronutrient metabolism, including storage, transport, and utilization, is altered in the presence of inflammation and oxidative stress. Inflammation results in increased production of acute-phase proteins such as ferritin, fibrinogen, and C-reactive protein, and decreased production of negative acute-phase proteins such as transferrin and retinol-binding protein. Because some negative acute-phase proteins transport micronutrients in the blood serum, a reduction in these proteins results in a decline in the serum concentration of the corresponding micronutrient. Inflammation also results in micronutrient redistribution to other organ systems, further reducing serum concentrations.1,2

Biochemical Markers
Obtaining serum vitamin and mineral levels can be a challenge in some hospitals, as these lab assays may not be available. Samples may need to be sent to an outside lab for some micronutrient biomarkers, delaying results. Even when labs are available, interpretation can be difficult in acute illness, as reduced levels are not necessarily indicative of a deficiency. Micronutrient deficiencies may not immediately manifest as altered serum biomarkers, as some levels remain normal until the later stages of deficiency.4

Considering the effect of inflammation on serum micronutrient levels, concomitant measurement of inflammatory markers such as C-reactive protein can help the RD estimate the degree of inflammation, providing a clue as to the potential impact of inflammation on the serum lab result.1-3 However, patients may have preexisting micronutrient deficiencies, thus it cannot be assumed an altered serum lab value is due solely to inflammation. Additionally, because of the shift in micronutrients from the blood to the organs, low serum levels may not indicate deficiency as the whole-body quantity of the nutrient remains the same. The recommended biomarker for some micronutrients is red blood cell concentration, rather than serum concentration, because blood cell levels are less likely to be affected by inflammation.3

Intake
Feeding regimens in the critically ill patient can be another confounding factor in micronutrient assessment. Patients who haven’t received adequate nutrition since admission—via oral, enteral, or parenteral routes—will have inadequate intake, potentially leading to or exacerbating micronutrient deficiencies. Clinicians should also be aware that micronutrient products used in parenteral nutrition solutions are frequently in short supply, resulting in inadequate intake of micronutrients for patients receiving this type of feeding.5 Further, intake from enteral nutrition may not be sufficient to meet 100% of the RDA for many micronutrients, also contributing to inadequate intake in the critically ill population.4 Oral intake prior to admission should also be assessed, if possible.

Medical History
Thoroughly reviewing the patient’s medical history can provide important clues in determining their risk or likelihood of having specific deficiencies. Conditions or procedures resulting in reduced nutrient absorption in the gastrointestinal tract, such as short bowel syndrome, inflammatory bowel disease, untreated celiac disease, and bariatric surgery, increase the risk of micronutrient deficiencies. Alcohol use disorder increases the probability of developing a deficiency, especially of B vitamins. Renal replacement therapy, including hemodialysis, peritoneal dialysis, and continuous renal replacement therapy, results in micronutrient losses, particularly of water-soluble vitamins. Medications use should also be reviewed, as many can alter micronutrient absorption, transport, and excretion.

Physical Examination
A nutrition-focused physical exam should be conducted to assess physical signs of micronutrient deficiencies, which can manifest as changes in the eyes, mouth, tongue, lips, skin, hair, and nails. Deficiency of some B vitamins can result in neurological abnormalities, including neuropathy, confusion, ataxia, and memory loss. The RD should be aware of differential diagnoses, as nonnutrient related issues can sometimes result in these signs and symptoms.

It should be noted that physical manifestations of micronutrient deficiencies, especially of fat-soluble vitamins, may take months or even years to develop, thus physical signs in the critically ill population more likely indicate a preexisting deficiency.6 Further, micronutrient status may be depleted, but not yet considered deficient, the stage at which clinical signs and symptoms are present.4 Micronutrients that are depleted are at higher risk of advancing to the deficient stage in the setting of critical illness.

Treating Deficiencies
Nutrition therapy for critically ill patients can be complex, and much is unknown regarding ideal feeding regimens to optimize clinical outcomes. The provision of macronutrients, including energy and protein, must be carefully managed with consideration for timing of feeding initiation, how much to provide, and when to hold feedings. Managing micronutrients—vitamins and minerals—is similarly complicated.

Interpreting the Literature
Several recently published systematic reviews and metanalyses have investigated randomly controlled trials (RCTs) on micronutrient supplementation in the ICU. Interpreting the results of multiple RCTs poses many challenges. The heterogeneity of patients, including differences in demographic factors such as age and sex, as well as disease state, medical and pharmacological treatments, and severity of illness, can make it difficult to come to meaningful conclusions. Further, differences in RCT design can also complicate results. Researchers may use different micronutrient doses, forms (ie, intravenous vs enteral), timing regimens (ie, number of times a day doses are given), and duration of the treatments. In some instances of research, even the way the micronutrients themselves are studied may differ. For example, some RCTs examine only one micronutrient such as thiamin, while others may investigate several B vitamins together.7

Some research has shown benefits in clinical outcomes with micronutrient supplementation in this population, while others have not. Therefore, there is no universally accepted consensus on this assessment and treatment of micronutrient deficiencies in the ICU population. Any research, including systematic reviews and metanalyses, should be interpreted with caution.

Dosing Considerations
Because water soluble vitamins are not stored in the body in any significant amounts and are rapidly excreted through the urine, supplementation of water-soluble vitamins is generally considered a low-risk treatment in most disease states. In some cases, supplementation is actually considered a standard treatment, most notably with thiamin and folate in patients with active alcohol use disorder. B vitamin supplementation is also common in patients receiving renal replacement therapy, as water soluble micronutrients are lost in dialysate. However, it should be noted that supplementation should be given cautiously in patients with renal disease who are not receiving renal replacement therapy, as decreased urine production will limit excretion of some micronutrients.2,4

By comparison, fat-soluble vitamins are stored in the body in greater amounts, thus deficiency can take much longer to develop. Because fat-soluble vitamins are not rapidly excreted like water soluble vitamins, more caution should be used when determining the supplemental dose, if it’s deemed safe to provide one at all. Many fat-soluble vitamins are stored in the liver; therefore, if they’re supplemented, dosing should be determined cautiously in patients with liver disease.2,4

Mineral supplementation should also be considered carefully. High doses or prolonged supplementation of one mineral may lead to deficiencies in another. Supplementation of either iron, copper, or zinc may reduce the absorption of the other two minerals.2,4

Specific Micronutrients
Select micronutrients especially relevant to the critical care patient are described below, including deficiency risk, assessment, and treatment.

Thiamin
Vitamin B1, also known as thiamin, is vital for carbohydrate metabolism, energy production, and synthesis of neurotransmitters, among other functions. Thiamin needs are elevated in critical illness, due in part to inflammation, thus increasing risk of deficiency. Malnutrition, poor oral intake, rapid refeeding after periods of inadequate intake, alcohol intake, and conditions which reduce absorption or increase losses also elevate the risk of deficiency. As a water-soluble vitamin with a short half-life, thiamin can become depleted rapidly, even in patients that enter the hospital with adequate thiamin stores.4

Deficiency may be characterized by neurological symptoms such as decreased cognition, confusion, and poor short-term memory, as well as congestive heart failure, among others. Supplemental thiamin is recommended in patients with encephalopathy of uncertain etiology; refeeding syndrome risk, especially those receiving parenteral nutrition; critical illness; and in those receiving continuous renal replacement or chronic diuretic therapies. Recently updated guidelines recommend 100 to 300 mg/d intravenous thiamin for three to four days for all ICU patients.4 Doses and duration of treatment may be higher depending on the risk factors and degree of deficiency.

Vitamin C
Vitamin C is a powerful antioxidant. In addition to its antioxidant functions, vitamin C plays a role in the production of neurotransmitters, cortisol, and collagen. Deficiency is associated with poor wound healing and impaired immune response. Researchers have theorized that because of its antioxidant properties, vitamin C supplementation may be of benefit in critically ill patients by attenuating the effects of severe inflammation. Numerous studies have been conducted in which vitamin C was supplemented, both as a monotherapy and in conjunction with thiamin and hydrocortisone. While some studies have yielded promising results, others have not. High intravenous supplemental vitamin C doses are necessary to increase serum levels to a normal or above normal range in critically ill patients; however, it is unclear if achieving normal serum levels is associated with positive clinical outcomes. Recent systematic reviews have suggested that current evidence is insufficient to recommend routine vitamin C supplementation in this population.7 In critical illness, guidelines suggest a dose of 2 to 3 g/day IV vitamin C during the acute phase of inflammation.4

Vitamin D
Vitamin D is a fat-soluble vitamin that plays a key role in regulating calcium and phosphorus levels, bone health, and glucose metabolism. Vitamin D deficiency has been associated with extended hospital length of stay in ICU patients and increased risk of sepsis and acute respiratory distress syndrome. As such, vitamin D supplementation has been studied in the critically ill population. Although research is mixed, some systematic reviews have suggested that vitamin D supplementation may lower mortality and ICU length of stay, with intravenous dosing having a stronger effect than enteral. Further research is needed to determine appropriate dosing and if positive results can be replicated. Determination of vitamin D status in critically ill patients is difficult as inflammation significantly reduces serum biomarkers. In consideration of this and uncertainties regarding dosing strategies, at present guidelines do not recommend routine supplementation of vitamin D in ICU patients.7

Zinc
Zinc plays a role in immune function and wound healing, is a cofactor for many enzymatic reactions, and modulates inflammation and oxidative stress. As such, zinc supplementation has been of interest in the treatment of critically ill patients. However, like many other micronutrients, serum levels drop significantly in the presence of inflammation, making assessment of zinc status challenging. Research on zinc supplementation is also difficult to interpret, especially because many studies have studied zinc in conjunction with other micronutrients. While ICU patients should receive the RDA for zinc, evidence for additional supplementation is lacking, therefore should not be administered except in the case of deficiency or high risk of deficiency.4

Key Takeaways
Micronutrient supplementation in critically ill patients is a complex issue. Serum levels of many micronutrients have been reported to be low in ICU patients; however, the presence of acute inflammation makes interpretation of biomarkers challenging. In addition to biomarkers and inflammation, it is important to consider micronutrient intake, medical history, and physical signs and symptoms when assessing micronutrient status. Although much research has been conducted, differences in study designs and populations also have confounded results. At this time, evidence for routine supplementation for most micronutrients, especially in the absence of deficiency or risk of deficiency is lacking. When and how to supplement micronutrients to yield the best clinical outcomes is unclear; further research is needed.

— Jennifer Doley, MBA, RD, CNSC, FAND, is a corporate malnutrition program manager with Morrison Healthcare. Previous roles include nutrition support specialist, clinical nutrition manager, regional clinical nutrition manager, and dietetic internship director. She is the coeditor of the book, Adult Malnutrition: Diagnosis and Treatment.

References
1. Dresden E, Pimiento JM, Patel JJ, et al. Overview of oxidative stress and the role of micronutrients in critical illness. J Parenter Enteral Nutr. 2022;47:S38-S49.

2. Roberts KM, Estes-Doetsch H, Nahikian-Nelms M, eds. Pocket Guide to Micronutrient Management. Academy of Nutrition and Dietetics; 2024.

3. Berger MM, Talwar D, Henkin A. Pitfalls in the interpretation of blood tests used to assess and monitor micronutrient nutrition status. Nutr Clin Pract. 2023;38(1):56-69.

4. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022;41(6):1357-1424.

5. Parenteral nutrition product shortages. American Society of Parenteral and Enteral Nutrition website. https://www.nutritioncare.org/Guidelines_and_Clinical_Resources/Parenteral_Nutrition_Product_Shortages/. Accessed December 16, 2024.

6. Modarsky B. Nutrition Focused Physical Exam, 3rd edition. Academy of Nutrition and Dietetics; 2022.

7. Halim Z, Huang Y, Lee ZY, et al. New randomized controlled trials on micronutrients in critical care nutrition: a narrative view. Nutr Clin Pract. 2024;39(5):1119-1149.