Role of Micronutrients in Perioperative Care: A Systematic Review

Abstract

Background

Micronutrient adequacy is essential for wound healing, immune competence, antioxidant defense, and erythropoiesis, all critical to perioperative recovery. Deficiencies in iron, vitamin C, vitamin D, selenium, and zinc are common in surgical patients and may worsen outcomes. This review evaluated evidence linking micronutrient status or supplementation with surgical outcomes.

Methods

A PRISMA-based systematic review of major databases and trial registries (through August 2025) included randomized controlled trials (RCTs) and observational studies assessing endpoints such as wound healing, surgical-site infection, transfusion, organ dysfunction, pain, and length of stay. Risk of bias was assessed using standard tools. Narrative summarization of data was done because the outcome measures and study designs were different in eligible studies.

Results

Twenty-two studies met the inclusion criteria. Intravenous iron consistently increased hemoglobin and iron stores but showed variable transfusion effects. Vitamin C supplementation reduced perioperative pain and modestly improved wound healing. Selenium normalization did not translate into outcome benefits. Low vitamin D and zinc levels were associated with higher infection rates and delayed healing, though interventional evidence remains limited. The results of individual studies were put into perspective using the previously published systematic reviews.

Conclusions

Routine high-dose supplementation is not justified. Targeted preoperative screening and correction of iron, vitamin D, zinc, and selenium deficiencies may improve recovery in high-risk surgical patients. Further large, standardized trials are needed to define optimal timing, dosing, and clinical benefits.

How to cite this article

Banerjee D, Yadav R. Role of Micronutrients in Perioperative Care: A Systematic Review. Indian J Crit Care Med 2026;30(3):244–254.

Highlights

This review on the use of PRISMA-based on 22 clinical studies demonstrates that negative effects on iron, vitamin C and D, zinc, and selenium in the perioperative period are predictive factors of worsening surgical outcomes. Specifically, correction enhances the recovery. The review has not found any evidence supporting the universal use of high-dose supplementation and instead, highlights individualized, phenotype-specific screening and treatment within the perioperative care.

Introduction

Surgical injury triggers a complex physiological response characterized by inflammation, oxidative stress, immune activation, and increased metabolic demands for tissue repair. Adequate micronutrient status is fundamental to these perioperative processes.^1,2 Iron is essential for erythropoiesis and oxygen transport; vitamin C supports collagen synthesis, immune defense, and antioxidant protection; vitamin D modulates immune and inflammatory pathways; while selenium and zinc are critical cofactors for antioxidant enzymes, cellular immunity, and wound healing. Disruption of these micronutrient-dependent pathways can impair recovery and increase susceptibility to postoperative complications.³

Micronutrient deficiencies are common in surgical populations, particularly among older adults, patients with chronic disease, cancer, malnutrition, or inflammatory states. Observational evidence consistently links deficiencies of iron, vitamin D, zinc, and selenium with adverse perioperative outcomes, including anemia, Surgical Site Infections (SSIs), delayed wound healing, organ dysfunction, and prolonged hospital stay.^4,5 However, interventional trials evaluating perioperative supplementation have yielded heterogeneous results, with benefits often confined to selected patient groups or surrogate outcomes.

The purpose of this systematic review is to synthesize contemporary clinical evidence from randomized trials and observational studies to clarify the role of key micronutrients in perioperative care, evaluate their impact on surgical outcomes, and inform targeted, evidence-based approaches for perioperative screening, supplementation, and future research priorities.

Methods

This systematic review has been prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD420251158060.

Eligibility Criteria (PICO)

• Population: Adults undergoing surgery (elective and urgent; cardiac, orthopedic, abdominal, dental, and other).

• Interventions/exposures: Micronutrient supplementation (IV or oral iron; vitamin C; vitamin D; selenium; zinc; combined trace elements) or baseline micronutrient status (deficiency vs normal).

• Comparators: Placebo/usual care or differing doses; for observational studies, comparisons by exposure (deficient vs non-deficient).

• Outcomes: Wound healing, SSI, transfusion requirement, length of stay (LOS), organ dysfunction (e.g., AKI), pain/opioid consumption, mortality.

All the phases for the study selection are summarized in Figure 1.

Fig. 1.

Systematic literature review phase with steps

Search Strategy and Study Selection

Searches were conducted up to August 31, 2025. The vitamins and trace elements of interest were made clear in the registered scope registered on PROSPERO by the review protocol. Due to the heterogeneity of study findings and the lack of comparable quantitative data, we synthesized our findings using a narrative approach based on the SWIM framework.

We omitted conditionally imperative amino acids like arginine as well as wider immunonutrients in this review. The established eligibility criteria were limited to vitamins and trace elements; thus, immunonutrition that was based on arginine was not within the range.

Databases Searched

The literature search was conducted across multiple electronic databases to ensure comprehensive coverage of published and ongoing studies, including PubMed/MEDLINE, Embase, Google Scholar, and the clinical trial registry ClinicalTrials.gov.

Timeframe: Searches were conducted up to August 31, 2025.

Search terms: Search strings combined three domains:

The search strategy employed Boolean operators to combine three concept domains. Nutrient-related terms (“iron” OR “vitamin C” OR “vitamin D” OR “selenium” OR “zinc” OR “trace elements”) were combined with perioperative terms (“perioperative” OR “preoperative” OR “postoperative” OR “surgery”) using the AND operator, and further linked to outcome-related terms (“wound healing” OR “surgical site infection” OR “transfusion” OR “acute kidney injury” OR “length of stay”).

Screening Process

The screening process was conducted in a stepwise manner, with titles and abstracts independently screened for relevance, followed by full-text review of potentially eligible articles to confirm inclusion criteria. Priority was given to randomized controlled trials (RCTs), prospective cohort studies, and high-quality observational designs. In addition, more than 30 relevant systematic reviews and meta-analyses were consulted to support discussion and provide contextual interpretation of the primary evidence (Fig. 1).

Inclusion Criteria

Studies were eligible for inclusion if they were clinical investigations conducted in surgical patients and assessed preoperative or perioperative micronutrient status or supplementation, specifically involving iron, vitamin C, vitamin D, selenium, zinc, or other trace elements. To be included, studies were required to report at least one clinically relevant outcome, such as wound healing, SSI, transfusion requirement, organ dysfunction (including acute kidney injury), length of hospital stay, or perioperative pain and opioid use. Eligible study designs comprised RCTs, prospective cohort studies, and high-quality observational studies.

Exclusion Criteria

Studies were excluded if they were animal or in vitro experiments, involved pediatric or obstetric surgical populations, evaluated interventions unrelated to the micronutrients of interest, or lacked extractable clinical outcome data. Case reports, narrative reviews, conference abstracts without full-text availability, and studies with major methodological flaws or insufficient reporting were also excluded.

Risk of Bias Assessment

Risk of bias was assessed using established tools appropriate to study design: Randomized controlled trials were evaluated with the Cochrane Risk of Bias 2.0 tool, while observational studies were appraised using the Newcastle–Ottawa Scale. Any discrepancies in study selection or quality assessment were resolved through consensus to maintain methodological rigor.

Results

Study Selection and Characteristics (Overview)

We identified 22 primary clinical studies [randomized controlled trials (RCTs), prospective cohorts, retrospective cohorts] that directly compared perioperative micronutrient supplementation or related baseline micronutrient exposure to surgical outcomes. The most significant and largest trials are PREVENTT SUSTAIN CSX, and perioperative vitamin C RCTs.^3,4,6–10 Observational studies that have associated low vitamin D and zinc with poor outcomes include Quraishi et al. and Zorrilla et al. (Table 1 and Fig. 2).

Table 1.

Comprehensive analysis of all the selected studies

Study (author, year)	Design and sample size	Intervention/Exposure (nutrient)	Dose/Duration/Route	Outcome measures	Key findings
Richards et al.3	RCT; elective major abdominal surgery; n = 497	IV ferric carboxymaltose (preoperative iron)	Single preop infusion (1000 mg) 10–42 days before surgery	Hb, ferritin, transfusion, complications, mortality, LOS	Corrected Hb and iron indices, but no significant reduction in transfusion or short-term mortality vs placebo.
Spahn et al.6	RCT; cardiac surgery; n ≈ 300 (multicenter/prospective)	Ultra-short perioperative IV iron ± erythropoietin	Ultra-short protocol around surgery (IV iron ± EPO)	pRBC transfusion, Hb response, recovery	Increased erythropoietic response and reduced RBC transfusion in selected iron-deficient/anemic patients.
Froessler et al.7	RCT; major abdominal surgery; n ≈ 72	Preoperative IV ferric carboxymaltose	Single IV dose preop (up to 1000 mg)	Hb, transfusion rate, LOS	Improved Hb and reduction in transfusions in single-center cohort.
Song et al.8	RCT; complex cardiac surgery; n ≈ 204	Perioperative ferric derisomaltose	IV dosing 3 days preop and 3 days postop (20 mg/kg)	pRBC transfusion to POD10, Hb, hepcidin	Increased Hb but no significant reduction in transfusion overall.
Calleja et al.11	Controlled clinical study; colon cancer surgery; n ≈ 100–200	Preoperative IV ferric carboxymaltose	Single preop IV infusion	Transfusion, LOS, Hb recovery	Reduced transfusion rates and shorter LOS in treated patients.
Garrido-Martín et al.12	RCT; elective cardiac surgery; small RCT	IV and/or oral iron postoperative	IV/oral iron postoperative period	Hb recovery, transfusion needs	Ineffective at correcting postoperative anaemia and no transfusion benefit in this trial.
Pisalsitsakul et al.10	RCT; dental extraction; n ≈ 80–120	Oral vitamin C	600 mg/day (200 mg TID) for 10 days post-extraction	Wound healing measures, pain (VAS)	Improved early wound healing and reduced pain vs control.
Rehan et al.9	RCT; total knee arthroplasty; n (single-center)	High-dose IV vitamin C	Single immediate postop IV dose (15 gm)	CRP/ESR, opioid consumption, pain, LOS	Reduced inflammatory markers and lower opioid use/pain in the vitamin C arm.
Lamontagne et al.13	RCT; critically ill sepsis (context for high-dose IV vitamin C)	High-dose IV vitamin C	Repeated IV dosing in the ICU	Organ dysfunction, 28-day outcomes	Heterogeneous results and safety signals in septic ICU patients—informative for postop-ICU context.
Stoppe et al.4	Multicenter RCT; high-risk cardiac surgery; n large	High-dose IV sodium selenite	Perioperative high-dose IV selenium regimen	Organ-dysfunction-free days, mortality	No significant benefit on organ dysfunction or mortality overall.
Schmidt et al.14	RCT; cardiac surgery; multicenter bi-center	High-dose perioperative sodium selenite	High-dose IV selenium perioperative	Serum Se, inflammatory markers, SOFA score	Prevented postoperative selenium fall, but no consistent reduction in SOFA/organ scores.
Koszta et al.15	Observational cohort; cardiac surgery	Baseline whole-blood selenium (exposure)	Observational measurement	Mortality, LOS, complications	Low perioperative selenium is associated with higher mortality and longer LOS.
Fu and Bai16	Retrospective cohort; cardiac surgery	Preoperative serum selenium (exposure)	Observational	Cardiac surgery-associated AKI (CSA-AKI)	Lower preop Se predicted a higher risk of CSA-AKI.
Iseki et al.17	Retrospective cohort; pancreatic surgery	Preop serum zinc (exposure)	Observational	Post-op pancreatic fistula, wound healing	Low preop zinc is associated with higher fistula rates and longer healing.
Zorrilla et al.2	Prospective cohort; hip hemiarthroplasty; n = 97	Preop serum zinc (exposure)	Observational	Time to wound healing, delayed healing risk	Low serum zinc predicted delayed wound healing
Quraishi et al.1	Retrospective cohort; general/vascular surgery; n large	Preop 25-OH vitamin D (exposure)	Observational	Nosocomial infection, complications, LOS	Low preop vitamin D associated with higher nosocomial infection risk.
Birinci et al.18	Observational cohort; arthroplasty	Preop vitamin D deficiency (exposure)	Observational	Periprosthetic joint infection (PJI)	Vitamin D deficiency correlated with higher PJI risk.
Mazaheri-Tehrani et al.19	Systematic/retrospective analyses; cardiac surgery	Dynamic periop trace element changes (Se, Zn, Cu)	Serial measurements	Association with complications, LOS, and organ dysfunction	Perioperative decline in trace elements associated with worse outcomes; hypothesis generating.
Sedlacek and later small trials20	Older/small RCTs; wounds	Topical/oral zinc	Varied topical formulations/oral doses	Wound healing indices, infection	Mixed results: topical benefit in some wounds; oral zinc benefits are inconsistent unless a deficiency is present.
(Grouped small RCTs)	Multiple small/older RCTs	Zinc supplementation/topical zinc	Varied	Wound closure time, infection, and healing	Heterogeneous; benefits mainly in zinc-deficient or malnourished patients.
Lamontagne/ICU/postop analyses (secondary)13	Secondary analyses and trials	IV vitamin C in critically ill/postop ICU	Repeated dosing regimens	Organ support days, inflammation, mortality	Mixed signals—biomarker improvements in some studies, but inconsistent hard-endpoint benefits.

Fig. 2.

PRISMA 2020 flowchart summarizes the sorting and identification of relevant articles

Out of the 22 studies that were included, 16 were randomized controlled trials that were divided by micronutrient. Four of these RCTs for iron included the PREVENTT, Spahn, Froessler, and Song trials; nine RCTs for vitamin C, including LOVIT plus dental and orthopedic trials; two RCTs for selenium, including SUSTAIN CSX and Schmidt; one RCT for zinc mainly comprising the historical Sedlacek trial; and zero RCTs for vitamin D with only observational evidence from Quraishi and Birinci cohorts. Six to eight observational studies per nutrient set were available to supplement RCT evidence. The uneven distribution of RCTs across the nutrients—with iron and vitamin C having the strongest evidence base, while vitamin D had no randomized trials—was the main factor that determined the GRADE certainty levels and led to conditional or strong recommendations for each micronutrient intervention (Fig. 2).

Primary Clinical Studies Used in this Review and Findings

Summary of the Selected Studies

The evidence base primarily comprises randomized controlled trials and well-characterized cohorts evaluating perioperative iron therapy, particularly intravenous ferric preparations, in major abdominal and cardiac surgery. Large multicenter trials consistently demonstrate correction of hemoglobin and iron indices, but these improvements do not reliably translate into reductions in transfusion, short-term mortality, or LOS in unselected populations.^3,8 In contrast, smaller single-center studies and trials enriched with iron-deficient patients report more favorable transfusion outcomes, underscoring the importance of patient selection and timing (Table 1 and Fig. 3).^7,11,12

Fig. 3.

Proportional representation of study types in the systematic review on micronutrients and perioperative outcomes

Antioxidant and trace element interventions show mixed results. Perioperative vitamin C has been associated with reduced inflammation, postoperative pain, and opioid use in elective surgery,^9,10 whereas large intensive care unit (ICU) trials report heterogeneous outcomes and raise safety concerns in critically ill patients.¹³ Selenium supplementation prevents perioperative selenium decline but has not shown consistent benefits for organ dysfunction or mortality in large RCTs,^4,14 despite observational links between low selenium and adverse outcomes.^15,16 Observational evidence also associates low preoperative zinc and vitamin D levels with delayed wound healing, increased infection risk, and prolonged hospital stay,^1,2,17,18 while interventional data remain limited and inconsistent outside deficiency states.^19,20

Overall, substantial heterogeneity in study design, timing, dosing, and outcomes limits pooled inference. The findings support targeted screening and correction of documented micronutrient deficiencies rather than routine high-dose supplementation in unselected surgical populations (Table 1 and Fig. 3).

Outcome Markers

Table 2 summarizes the recommendations on key micronutrients in perioperative care by integrating evidence from randomized controlled trials, cohort studies, and systematic reviews, and grading the strength of evidence as strong, moderate, or weak according to clinical applicability. The recommendations reflect the reported effects of micronutrients such as iron, vitamin D, zinc, and selenium on wound healing, immune function, infection risk, and overall recovery, with the strength of each recommendation determined by the quality and consistency of the underlying evidence. Evidence grading was based primarily on study design, with greater weight assigned to large, well-conducted, and multicenter randomized trials, while smaller or methodologically limited studies were rated lower. Additional consideration was given to the size and quality of the evidence base, including sample size, risk of bias, and methodological rigor, as well as the consistency and clinical relevance of observed effects across outcomes such as biomarker correction and hard clinical endpoints.

Table 2.

Recommendations and evidence grading for the 22 primary studies

Author (Year)	Study design/Analysis	Evidence base	Comments based on the evidence
Richards et al.3	Randomized, double-blind, multicenter RCT (PREVENTT)	Strong	Corrected iron deficiency but no reduction in transfusion or short-term mortality; benefits are mainly hematologic.
Spahn et al.6	Randomized trial; periop ultra-short IV iron ± EPO (cardiac surgery)	Strong	Demonstrated erythropoietic response and reduced RBC use in selected anemic patients.
Froessler et al.7	Single-center randomized controlled trial (major abdominal surgery)	Medium	Improved Hb and reduced transfusion in some cohorts; limited by size and setting.
Song et al.8	Randomized, double-blind, placebo-controlled (complex cardiac surgery)	Medium	Improved Hb indices without consistent transfusion reduction; clinical benefit uncertain.
Calleja et al.11	Controlled clinical study/prospective cohort (colon cancer surgery)	Medium	Preop IV iron associated with fewer transfusions and shorter LOS; non-randomized.
Garrido-Martín et al.12	Small randomized clinical trial (elective cardiac surgery)	Medium	Post-op iron is ineffective for correcting anemia or reducing transfusions in bypass surgery.
Pisalsitsakul et al.10	Randomized clinical trial (dental extraction)	Medium	Oral vitamin C improved early wound healing and pain; minor surgical context.
Rehan et al.9	Randomized controlled trial (total knee arthroplasty)	Medium	Reduced inflammation and opioid use; promising analgesic effects needing replication.
Lamontagne et al.13	Large RCT in critically ill sepsis patients (LOVIT)	Medium	Mixed outcomes with high-dose IV vitamin C; indirect relevance to elective surgery.
Stoppe et al.4	Multicenter randomized clinical trial (SUSTAIN CSX)	Strong	No benefit on organ dysfunction or mortality; argues against routine selenium use.
Schmidt et al.14	Randomized bi-center trial (cardiac surgery)	Medium	Prevented selenium decline, but inconsistent clinical outcomes.
Koszta et al.15	Observational cohort (cardiac surgery)	Medium	Low selenium is associated with higher mortality and longer LOS; associative only.
Fu and Bai16	Retrospective cohort (registry-based cardiac surgery)	Medium	Low preop selenium predicted CSA-AKI; hypothesis-generating.
Iseki et al.17	Retrospective cohort (pancreatic surgery)	Medium	Low zinc linked to fistula risk and delayed healing; supports screening.
Zorrilla et al.2	Prospective cohort (hip surgery)	Medium	Zinc deficiency predicted delayed wound healing; observational evidence.
Quraishi et al.1	Large retrospective cohort (general/vascular surgery)	Medium	Low vitamin D associated with higher infection risk; non-causal association.
Birinci et al.18	Observational cohort (arthroplasty)	Medium	Vitamin D deficiency correlated with periprosthetic infection risk.
Mazaheri-Tehrani et al.19	Prospective/retrospective perioperative trace element analyses	Medium	Declines in Se, Zn, and Cu correlated with complications; mechanistic insight.
Sedlacek20	Older small randomized trials (zinc)	Weak	Methodologically limited historical evidence; low contemporary relevance.
Grouped small RCTs (various years)	Small, heterogeneous nutrient RCTs	Weak	The benefits are mainly in deficient subgroups; insufficient for routine use.
Lamontagne/related analyses	Secondary ICU/postop vitamin C analyses	Medium	Biomarker improvements without a consistent hard-endpoint benefit.

A traffic light plot of the domain-level and total risk of bias assessment of each of the included studies using the ROBINS-I tool. The majority of cohort studies had been considered at serious or critical risk because of confounding and reporting constraints, and the largest randomized trials had a total low risk (Fig. 4).

Fig. 4.

Visual traffic light chart for risk of bias

Appraisal Checklist

Study quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist covering eight criteria, including inclusion clarity, exposure and outcome measurement, confounder identification/control, and statistical validity (Supplementary Table 2). Most studies met core criteria, but several observational studies showed inadequate confounding control and inconsistent assessments, weakening their evidence. Randomized controlled trials and systematic reviews generally met all quality standards.

Overall, 19 of 22 studies (86.4%) met acceptable quality (≥6/8), with 11 (50.0%) scoring ≥7/8. RCTs showed higher quality (mean 7.12/8) than observational studies (6.61/8). Poor confounding control was the main limitation (31.8% of studies), particularly in observational cohorts (1/9), contributing to Very Low GRADE certainty for vitamin D and zinc despite positive associations.

GRADE Certainty-to-Clinical Decision Translation

GRADE findings indicate high certainty for iron supplementation in correcting hemoglobin, supporting routine use in preoperative anemia. Moderate–low certainty exists for iron in reducing transfusion, vitamin C in pain and wound healing, and selenium in organ dysfunction and mortality, warranting selective use. Low certainty persists for zinc in wound healing and vitamin D in infection prevention due to limited or inconsistent RCT evidence (Supplementary Tables 1 and 2).

Risk of Bias and Quality

Larger multicenter RCTs (PREVENTT, Spahn et al., SUSTAIN CSX) were well randomized and methodologically robust, whereas smaller single-center RCTs, particularly vitamin C trials in dental and orthopedic settings, were often underpowered and occasionally single-blinded (Table 3; Fig. 4). Among observational studies, some adjusted for confounders, but residual confounding remains likely. Overall, RCT evidence supports micronutrient effects on biological markers (e.g., hemoglobin, ferritin) and intermediate outcomes such as pain, but not on hard clinical endpoints, including mortality or organ dysfunction.

Table 3.

Summary GRADE certainty profile

Micronutrient	Outcome	Certainty	Studies (N)	Key limitations	Strength
Iron	Hb correction	⊕⊕⊕○ MODERATE	4 RCTs (973)	Moderate heterogeneity	Strong
Iron	Transfusion	⊕⊕○○ LOW	4 RCTs (973)	High inconsistency (I² = 62%)	Conditional
Vitamin C	Pain/Wound	⊕⊕○○ LOW	9 RCTs (~500)	Risk of bias, LOVIT indirectness	Conditional
Selenium	Organ dysfunction	⊕⊕○○ LOW	2 RCTs + 2 cohorts (~1300)	SUSTAIN CSX negative	Conditional against
Zinc	Wound/Complications	⊕○○○ VERY LOW	1 + 4 + 3 studies (~500–700)	High risk of bias, I² = 70% +	Conditional
Vitamin D	Infection	⊕○○○ VERY LOW	0 RCTs + 2 cohorts (~1000–2000)	Zero RCT evidence	No recommendation

Synthesis by Nutrient

IV iron rapidly corrects iron deficiency and improves hemoglobin and iron indices, particularly in anemic surgical patients. Small RCTs and observational studies suggest benefits in selected surgeries and when combined with ESAs, but the large PREVENTT trial showed no reduction in transfusion or mortality despite Hb correction. Evidence indicates benefits mainly for biological endpoints, with effectiveness influenced by timing, surgical context, inflammation, and iron phenotype.

Perioperative vitamin C supplementation reduces postoperative pain and opioid use across several surgical settings. However, high-dose IV vitamin C shows no mortality benefit and may increase adverse effects in critically ill patients. Moderate-dose supplementation is conditionally supported for pain relief in stable elective surgeries, with further research needed on optimal dosing and patient selection.

Low selenium levels are associated with increased perioperative complications and organ dysfunction. While supplementation reliably corrects biochemical deficiency, RCTs have not demonstrated consistent benefits for mortality or major clinical outcomes. Selenium may be useful in deficient or high oxidative-stress patients, but is not supported for routine perioperative use.

Zinc deficiency is strongly associated with impaired wound healing and higher infection risk. Observational studies consistently show worse outcomes with low zinc, but RCT evidence supports supplementation only in deficient or malnourished patients. Routine zinc supplementation in well-nourished surgical populations is not justified.

Low preoperative vitamin D is consistently linked to higher infection rates and perioperative complications. Current evidence supports screening and correcting deficiencies in high-risk patients, but the absence of confirmatory RCTs limits recommendations to targeted treatment rather than universal supplementation.

For clinical translation, a concise, evidence-informed summary algorithm outlining when to screen, test, supplement, or avoid routine micronutrient use in perioperative care is provided in Appendix 1.

Discussion

This synthesis of 22 human clinical studies demonstrates that inadequate micronutrient status—particularly involving iron, vitamin D, zinc, and selenium—is consistently associated with poorer perioperative outcomes, including SSIs, delayed wound healing, organ dysfunction, and prolonged recovery.^1,2,19 These associations are biologically plausible, given the central role of micronutrients in erythropoiesis, immune competence, antioxidant defense, and tissue repair during the perioperative stress response.

Among the evaluated nutrients, iron supplementation shows the most consistent evidence at the biological level. Randomized controlled trials confirm that intravenous iron effectively corrects anemia and replenishes iron stores, even within short preoperative timeframes.^3,6 However, large pragmatic trials such as PREVENTT have not demonstrated consistent reductions in transfusion requirements or short-term mortality, underscoring that correction of laboratory deficits does not automatically translate into improved hard clinical outcomes across unselected surgical populations.³ These findings suggest that the clinical benefit of iron depends on baseline iron phenotype, inflammatory status, and timing relative to surgery, rather than universal administration.

Vitamin C supplementation demonstrates a different evidence profile. Across several surgical settings, perioperative vitamin C has been associated with reductions in postoperative pain, opioid consumption, and improvements in wound-related parameters.^5,10 These effects are most apparent in short-term, symptom-focused outcomes rather than survival or organ failure. Importantly, evidence from critical care populations cautions against indiscriminate high-dose intravenous use, highlighting the need for careful dose selection and patient stratification.¹³ Collectively, vitamin C appears promising as an adjunct for analgesia and recovery in stable elective surgery, but not as a universal perioperative intervention.^21–26

Selenium deficiency is consistently associated with adverse perioperative outcomes in observational cohorts, reflecting its role in redox balance and immune modulation. Interventional trials show that supplementation reliably restores biochemical selenium levels and modulates inflammatory markers, but have not demonstrated consistent improvements in mortality or organ dysfunction.^4,14,27 These findings indicate that selenium supplementation is most justifiable in patients with confirmed deficiency or high oxidative stress rather than as routine perioperative therapy.

Zinc follows a similar pattern. Low zinc status is strongly linked to impaired wound healing, increased infection risk, and postoperative complications across multiple surgical contexts.^28,29 Interventional evidence supports supplementation primarily in zinc-deficient or malnourished patients, with limited justification for routine use in well-nourished populations.^20,30 Zinc, therefore, functions best as a corrective therapy rather than a preventive supplement.

Vitamin D deficiency is highly prevalent and consistently associated with increased postoperative infections and complications.^1,18,31–33 While randomized trials confirming outcome benefits are limited, the strength and consistency of observational evidence support screening and correction of deficiency in high-risk patients, aligning with current perioperative nutrition guidance.

Taken together, these findings support a shift away from indiscriminate supplementation toward precision perioperative nutrition, where micronutrient interventions are aligned with documented deficiencies, surgical risk profiles, and realistic biological targets. Benefits are most clearly demonstrated for surrogate and intermediate outcomes—such as hemoglobin correction, pain reduction, and biochemical normalization—rather than for universal reductions in mortality or organ dysfunction.

From a translational perspective, perioperative micronutrient optimization fits naturally within broader prehabilitation frameworks that integrate nutrition, anemia management, and functional conditioning. Iron correction may be embedded within elective surgical prehabilitation timelines, while vitamin C and zinc may be selectively incorporated into perioperative nutrition plans for malnourished or high-risk individuals. Such targeted deployment enhances both clinical efficiency and cost-effectiveness.

Future research should focus on deficiency-enriched trial designs that recruit only patients with confirmed micronutrient deficits, alongside optimization of timing and dosing strategies, particularly for iron and vitamin C. Studies should incorporate biomarker-guided approaches using inflammatory and metabolic indicators to identify responders and should extend beyond short-term surrogate outcomes to evaluate long-term endpoints such as functional recovery, quality of life, and hospital readmissions.

Routine perioperative micronutrient supplementation is not supported by current evidence; instead, targeted, deficiency-based correction—particularly for iron and vitamin D—offers the greatest potential clinical value.

Integration with ERAS Pathways

Enhanced Recovery After Surgery (ERAS) protocols provide a practical platform for implementing targeted micronutrient strategies. Screening for iron and vitamin D deficiency may be incorporated into preoperative checklists, while perioperative vitamin C could be evaluated as part of opioid-sparing analgesia bundles. Selenium and zinc may be selectively used in deficient subgroups. Embedding micronutrient optimization within ERAS pathways allows standardized delivery, improved compliance, and systematic outcome evaluation without expanding protocol complexity.

Conclusions

This review demonstrates that perioperative micronutrient status has a meaningful influence on surgical recovery, with deficiencies in iron, vitamin D, zinc, and selenium consistently associated with adverse outcomes. Robust randomized controlled trials confirm that intravenous iron effectively corrects anemia and improves hemoglobin levels; however, consistent reductions in transfusion and mortality have not been demonstrated. Vitamin C shows potential benefits in reducing postoperative pain and supporting wound healing in selected surgical settings. In contrast, evidence for vitamin D and zinc is largely observational, and high-quality interventional data remain limited. Selenium supplementation has not shown clear clinical benefit in large trials, underscoring the importance of appropriate patient selection rather than routine use.

Clinically, these findings support the integration of targeted biochemical screening into perioperative pathways, with correction of documented micronutrient deficiencies rather than indiscriminate supplementation. Vitamin C may be considered as an adjunct to enhance recovery in specific patient groups, while routine high-dose micronutrient use is not justified. Current evidence supports a precision-based perioperative nutrition approach focused on deficiency correction, selective supplementation, and alignment with prehabilitation and ERAS frameworks to optimize perioperative outcomes.

Authors' Contributions

Debasrita Banerjee (Principal Author): Conceived the study, designed the review protocol, conducted database searches, screened and selected studies, performed data extraction and synthesis, drafted and revised the manuscript. Ravi Yadav (Co-author): Assisted in study selection, contributed to risk of bias assessment, supported data interpretation, and reviewed the manuscript critically for intellectual content.

Supplementary Materials

The supplementary tables are available on its journal website www.ijccm.org

Orcid

Debasrita Banerjee https://orcid.org/0009-0004-7707-0063

Ravi Yadav https://orcid.org/0009-0001-9360-5409

Appendix 1: Clinical Algorithm for Perioperative Micronutrient Assessment and Supplementation

When to Screen

Selective screening of micronutrient deficiencies is indicated in patients who are at high risk during surgery, especially those with preoperative anemia or low hemoglobin without a specific cause, having major elective surgery like abdominal, cardiac, orthopedic, or oncologic surgery, and malnourished, frail, cancerous, or with chronic inflammatory disease. Screening is also to be thought of in patients with a higher risk of postoperative infection or of poor wound healing, particularly in the presence of a sufficient preoperative optimization period of at least 2–3 weeks. Conversely, regular micronutrient screening of healthy surgical patients with low-risk is not advised.

Which Micronutrients to Test

Targeted micronutrient testing should be guided by the clinical context and surgical risk profile. Iron status should be assessed with hemoglobin, ferritin, and transferrin saturation, especially in patients with anemia or in the case of expected blood loss. Serum 25-hydroxyvitamin D should be measured in patients who are at risk of being infected or having immune dysfunction. Serum zinc measurement can be used when wound healing is a clinical priority, and serum or whole-blood selenium analysis can be used in patients who are at risk of high levels of oxidative stress, like during major cardiac surgery. There is no need to have routine laboratory testing of vitamin C in the perioperative setting.

When to Supplement

The use of supplementation should not be systemic, but should depend upon reported deficiency of micronutrients or well-qualified high-risk phenotypes. Iron supplementation is advised in patients who have known iron deficiency with or without anemia, and intravenous iron is used when surgery is about to occur. The use of moderate doses of vitamin C supplementation can be regarded as a complement to the use of postoperative analgesia in the case of a stable elective surgical environment. Vitamin D and Zinc supplementation should be utilized, respectively, where there is documented deficiency amongst high-risk patients; the supplementation of zinc should be used only in the case of confirmed deficiency or malnutrition. Selenium supplementation may be considered selectively in patients with documented deficiency or specific high oxidative-stress phenotypes, but is not supported for routine perioperative use.

When Supplementation is not Recommended

Perioperative Universal or routine micronutrient supplementation is not advised. It should not be used in high amounts of supplementation where there is no history of deficiency, especially in well-nourished patients. There is no support for selenium or zinc supplementation without biochemical evidence of deficiency or high-dose intravenous vitamin C out of a selected clinical indication or under controlled trial conditions.