The Biology of Wound Healing and Nutrition in the ICU

A Comprehensive Review for Critical Care Postgraduates

Dr Neeraj Manikath , claud.ai

Introduction

Wound healing in the critically ill patient represents one of the most challenging clinical scenarios in intensive care medicine. The convergence of metabolic derangements, systemic inflammation, hemodynamic instability, and iatrogenic factors creates a perfect storm that disrupts the intricate biological cascade of tissue repair. Understanding the interplay between wound biology and nutritional support is not merely academic—it directly impacts patient outcomes, ICU length of stay, and long-term morbidity.

This review synthesizes current evidence on wound healing biology in critical illness and provides practical guidance for optimizing nutritional strategies in ICU patients with complex wounds.

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The Phases of Healing and Critical Illness Disruption

1. The Inflammatory Phase (Days 0-5)

Normal Physiology: The inflammatory phase begins immediately upon injury with hemostasis and platelet aggregation. Platelets release growth factors including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF). Within hours, neutrophils infiltrate the wound, followed by monocytes that differentiate into macrophages—the orchestrators of wound healing.[1,2]

Critical Illness Disruption:

The ICU patient faces multiple barriers during this crucial phase:

• Prolonged Inflammation: Sepsis and systemic inflammatory response syndrome (SIRS) create a state of persistent hyperinflammation. Elevated levels of pro-inflammatory cytokines (IL-1, IL-6, TNF-α) prevent the normal transition to the proliferative phase.[3]

• Impaired Neutrophil Function: Despite elevated neutrophil counts, critical illness induces neutrophil dysfunction with impaired chemotaxis, phagocytosis, and bacterial killing. This phenomenon, termed "immunoparalysis," increases infection risk while paradoxically maintaining inflammation.[4]

• Tissue Hypoxia: Shock states, whether septic, cardiogenic, or hemorrhagic, compromise tissue oxygen delivery. Since neutrophil respiratory burst and macrophage function are oxygen-dependent, hypoxia severely impairs the inflammatory response.[5]

Pearl: Check hemoglobin A1c in all patients with delayed wound healing—undiagnosed diabetes profoundly affects the inflammatory phase through impaired neutrophil function and increased advanced glycation end-products.

2. The Proliferative Phase (Days 4-21)

Normal Physiology: This phase is characterized by angiogenesis, granulation tissue formation, re-epithelialization, and collagen deposition. Fibroblasts migrate into the wound matrix and begin synthesizing collagen (primarily type III initially). Simultaneously, endothelial cells form new capillary networks in response to VEGF and basic fibroblast growth factor (bFGF).[2,6]

Critical Illness Disruption:

• Protein Catabolism: Critical illness induces a hypercatabolic state with protein breakdown rates of 1.5-2.0 g/kg/day. Negative nitrogen balance impairs collagen synthesis, as collagen requires glycine, proline, and hydroxyproline—amino acids derived from dietary protein.[7]

• Insulin Resistance and Hyperglycemia: Stress-induced hyperglycemia (even in non-diabetics) impairs fibroblast proliferation and collagen synthesis. Elevated glucose levels also compromise neutrophil function and promote infection through glycosylation of proteins.[8]

• Medication Effects: Commonly used ICU medications profoundly affect this phase. Vasopressors reduce tissue perfusion; corticosteroids inhibit fibroblast proliferation and collagen synthesis; neuromuscular blockers contribute to muscle wasting and protein depletion.[9]

• Micronutrient Deficiencies: Critical illness depletes zinc, vitamin C, and vitamin A—all essential cofactors for collagen synthesis and fibroblast function.

Oyster: Beware of overfeeding during this phase. Excessive caloric provision (>30 kcal/kg/day) can worsen hyperglycemia, increase CO₂ production, and promote hepatic steatosis without improving wound healing. "More is not better" applies to ICU nutrition.[10]

3. The Maturation/Remodeling Phase (Days 21 to 1-2 Years)

Normal Physiology: During maturation, type III collagen is gradually replaced by stronger type I collagen. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) carefully balance collagen degradation and synthesis. Wound tensile strength progressively increases, reaching approximately 80% of original tissue strength by 12 weeks.[2]

Critical Illness Disruption:

• Prolonged Catabolism: Many ICU survivors experience persistent catabolism and sarcopenia during recovery, limiting substrate availability for collagen remodeling.[11]

• Chronic Inflammation: Post-intensive care syndrome (PICS) involves ongoing low-grade inflammation that disrupts the MMP/TIMP balance, potentially leading to excessive scarring or chronic wound formation.[12]

• ICU-Acquired Weakness: Neuromuscular complications affect mobility, reducing mechanical stress on healing tissues—a necessary stimulus for proper collagen alignment and tensile strength development.

Hack: For patients with large abdominal wounds post-laparotomy, progressive tension sutures or negative pressure wound therapy (NPWT) provides the mechanical stress needed to guide collagen remodeling and prevent excessive scarring or dehiscence.[13]

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The Specific Roles of Key Nutrients

Arginine: The Conditionally Essential Immune Modulator

Biological Role: Arginine serves as substrate for nitric oxide synthase (NOS), producing nitric oxide (NO)—crucial for wound healing through vasodilation, angiogenesis, and collagen synthesis. Arginine also stimulates T-cell function, enhances wound collagen deposition, and promotes growth hormone secretion.[14,15]

Critical Care Considerations:

During critical illness, arginine becomes "conditionally essential" as endogenous production cannot meet increased demands. Studies demonstrate that arginine supplementation (12-30 g/day) improves nitrogen balance and may enhance immune function in surgical patients.[14]

The Controversy: The use of arginine in septic patients remains contentious. Early concerns arose from studies suggesting arginine might worsen outcomes in sepsis through excessive NO production, potentially exacerbating vasodilation and hypotension. However, recent meta-analyses show no harm in critically ill surgical patients, though benefit in medical sepsis remains unproven.[16]

Clinical Pearl: Consider arginine supplementation (15-20 g/day) in:

• Major elective surgery patients (preoperatively and postoperatively)
• Trauma patients without severe sepsis
• Burn patients (proven benefit)
• Large surgical wounds or enterocutaneous fistulas

Avoid in:

• Severe septic shock requiring high-dose vasopressors
• Significant hepatic dysfunction (risk of hyperammonemia)
• Renal failure without renal replacement therapy

Glutamine: The Gut and Immune Fuel

Biological Role: Glutamine is the most abundant amino acid in the body and primary fuel source for enterocytes, lymphocytes, and rapidly dividing cells including fibroblasts. It maintains gut barrier integrity, modulates inflammatory responses, and serves as a nitrogen shuttle between tissues.[17]

Depletion in Critical Illness: Plasma glutamine levels fall by 30-50% in critical illness due to increased consumption by immune cells and splanchnic tissues, coupled with reduced skeletal muscle synthesis (the primary glutamine reservoir).[18]

The Evidence Evolution: Early studies (including the famous Swedish study by Wernerman) suggested benefit from parenteral glutamine (0.3-0.5 g/kg/day). However, the landmark REDOXS trial (2013) demonstrated increased mortality with high-dose glutamine (0.35 g/kg/day IV + 30 g/day enteral) in patients with multiorgan failure and shock.[19]

Current Recommendations:

• Don't supplement in severe septic shock or multiorgan failure
• Consider supplementation (0.3-0.5 g/kg/day) in:
  • Burns >20% TBSA
  • Trauma patients (ISS >20)
  • Major GI surgery with prolonged ileus
  • Patients requiring exclusive parenteral nutrition

Hack: Most standard enteral formulas contain adequate glutamine (4-8 g/L). Before adding supplemental glutamine, calculate what the patient is already receiving through enteral nutrition.

Zinc: The Wound Healing Catalyst

Biological Role: Zinc serves as cofactor for >300 enzymes, including those essential for DNA synthesis, cell division, and protein synthesis. Specifically for wound healing, zinc is required for:

• Collagenase activity (MMP function)
• Keratinocyte migration and proliferation
• Immune cell function
• Antioxidant defense (superoxide dismutase cofactor)[20]

ICU Zinc Deficiency: Critical illness increases urinary zinc losses through stress hormones and inflammatory cytokines. Additionally, zinc redistribution occurs as an acute phase response. Studies show 30-50% of ICU patients have zinc deficiency.[21]

Clinical Signs of Deficiency:

• Delayed wound healing
• Alopecia
• Diarrhea
• Impaired taste (though difficult to assess in intubated patients)
• Pustular rash (acrodermatitis enteropathica-like)

Supplementation Strategy:

• Prophylactic: 15-20 mg/day (RDA) in standard ICU multivitamins
• Therapeutic (confirmed deficiency): 40-50 mg elemental zinc daily for 2-4 weeks
• Chronic wounds/fistulas: 25-40 mg/day ongoing

Oyster: Excessive zinc supplementation (>50 mg/day chronically) impairs copper absorption and can paradoxically worsen immune function. Always monitor for copper deficiency in long-term high-dose zinc therapy.

Pearl: Patients with high-output enterocutaneous fistulas lose approximately 12 mg zinc per liter of fistula output. Calculate and replace accordingly.

Vitamin C (Ascorbic Acid): The Collagen Crosslinker

Biological Role: Vitamin C is an absolute requirement for collagen synthesis, serving as cofactor for prolyl hydroxylase and lysyl hydroxylase—enzymes that hydroxylate proline and lysine residues in procollagen. Without adequate vitamin C, collagen molecules cannot form stable triple helices, leading to scurvy.[22]

Beyond collagen synthesis, vitamin C:

• Functions as powerful antioxidant
• Enhances neutrophil chemotaxis and phagocytosis
• Supports endothelial barrier function
• Facilitates iron absorption

The Sepsis-Vitamin C Story: The CITRIS-ALI trial and subsequent studies explored high-dose intravenous vitamin C (50 mg/kg q6h, up to 200 mg/kg/day) in septic patients, showing mixed results on mortality but consistent trends toward improved organ function scores.[23]

For Wound Healing Specifically: Standard recommendations suggest 500-1000 mg/day for patients with large wounds or pressure injuries, significantly higher than the RDA (90 mg for men, 75 mg for women).[24]

Clinical Application:

• Prophylactic: 200-500 mg/day in all ICU patients
• Active wound healing: 1-2 g/day divided doses
• Burns/major trauma: 1-2 g/day
• Suspected deficiency: 1 g daily until replete

Hack: Signs of subclinical vitamin C deficiency in the ICU include:

• Perifollicular hemorrhages
• Corkscrew hairs
• Poor wound healing despite adequate protein
• Unexplained petechiae or ecchymoses

Pearl: Patients receiving continuous renal replacement therapy (CRRT) lose significant vitamin C in the ultrafiltrate. Consider doubling the daily dose in CRRT patients.

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Clinical Application: Designing Specialized Nutrition Plans

Case Scenario 1: The Burn Patient

A 45-year-old male with 40% TBSA mixed partial and full-thickness burns, requiring mechanical ventilation and multiple debridements.

Nutritional Strategy:

1. Energy Requirements:

   • Calculate using modified Curreri formula: 25 kcal/kg + (40 kcal × %TBSA)
   • For 80 kg patient: (25 × 80) + (40 × 40) = 3,600 kcal/day
   • Adjust based on indirect calorimetry if available (gold standard)

2. Protein Requirements:

   • Burns require 1.5-2.0 g/kg/day (some sources suggest up to 2.5 g/kg for >20% TBSA)
   • Target: 150-180 g protein/day
   • Monitor prealbumin every 3-4 days (despite acute phase reactant limitations)

3. Micronutrient Supplementation:

   • Vitamin C: 1-2 g/day (proven benefit in burns)
   • Zinc: 40 mg/day for first 2 weeks, then 20 mg/day
   • Vitamin A: 10,000 IU daily (epithelialization support)
   • Selenium: 200-400 mcg/day (antioxidant)
   • Copper: 2-5 mg/day (lysyl oxidase cofactor for collagen crosslinking)

4. Immunonutrition:

   • Glutamine: 0.3-0.5 g/kg/day IV if on parenteral nutrition
   • Arginine: 15-20 g/day (high-quality evidence in burns)
   • Omega-3 fatty acids: 0.15-0.2 g EPA+DHA/kg/day

5. Route:

   • Enteral nutrition (gastric or post-pyloric) initiated within 24-48 hours
   • Start at trophic rates (20-30 mL/hr) and advance as tolerated
   • Parenteral supplementation if unable to meet >60% goals by day 7

Monitoring:

• Daily nitrogen balance (if urine collection possible)
• Twice-weekly prealbumin and CRP
• Weekly zinc and selenium levels
• Wound assessment with photography

Hack: Burns increase metabolic rate by approximately 10% per %TBSA burned (up to 40% TBSA, then plateaus). Expect energy requirements to decrease by 10-20% after definitive wound coverage with skin grafts.

Case Scenario 2: Enterocutaneous Fistula with High Output

A 60-year-old female with postoperative enterocutaneous fistula draining 1,200 mL/day of small bowel content following complicated Crohn's disease surgery.

Nutritional Strategy:

1. Fistula Classification:

   • High-output (>500 mL/day)
   • Proximal small bowel location (based on electrolyte composition)
   • Likely requires bowel rest and TPN

2. Energy and Protein:

   • Standard ICU calculations: 25-30 kcal/kg IBW
   • Protein: 1.5-2.0 g/kg (increased losses through fistula)
   • For 70 kg patient: 1,750-2,100 kcal, 105-140 g protein

3. Fluid and Electrolyte Replacement:

   • Replace fistula output mL-for-mL with balanced crystalloid
   • Small bowel fluid composition: Na 100-140, K 5-15, Cl 90-120, HCO₃ 30-40 (mmol/L)
   • Consider 0.9% saline with 20-40 mEq/L KCl

4. Specific Micronutrient Losses:

   • Zinc: 12 mg/L fistula output = 14.4 mg/day loss → supplement 40-50 mg/day
   • Magnesium: Often depleted → supplement 400-500 mg/day
   • Selenium, chromium, manganese: Include in TPN trace elements

5. Specialized TPN Formulation:

   • Amino acids: 1.5-2.0 g/kg
   • Lipids: 1.0-1.5 g/kg (30-40% of non-protein calories)
   • Dextrose: remaining calories
   • Glutamine additive: 0.3-0.5 g/kg/day (maintaining gut barrier despite bowel rest)
   • Double-dose multivitamins
   • Vitamin K: 10 mg weekly (if on TPN >7 days)

6. Adjunct Therapies:

   • Octreotide 100-200 mcg SC q8h (reduce fistula output)
   • Proton pump inhibitor (reduce gastric volume)
   • Loperamide via Replogle tube if feasible

Pearl: The "fistula closure algorithm":

• Sepsis control (drainage/debridement)
• Skin protection (ostomy nursing/wound care)
• Nutrition optimization (TPN, micronutrients)
• Spontaneous closure occurs in 30-40% by 4-6 weeks with optimal nutrition
• Surgical intervention for remainder after 6-12 weeks of optimization

Hack: Use chromium levels to assess for deficiency in long-term TPN patients with fistulas. Chromium deficiency presents with glucose intolerance, peripheral neuropathy, and impaired wound healing—all mimicking critical illness effects.

Case Scenario 3: Large Abdominal Wound (Open Abdomen)

A 55-year-old male with open abdomen following damage control laparotomy for perforated diverticulitis, NPWT in place.

Nutritional Challenges:

• Protein losses through wound exudate: 50-100 g/day
• Fluid evaporation: 1-2 L/day
• Increased metabolic demands from ongoing inflammation
• Often concurrent with ileus, limiting enteral nutrition

Nutritional Strategy:

1. Dramatically Increased Protein Requirements:

   • Baseline 1.5 g/kg + wound losses
   • NPWT foam contains 20-30 g protein when saturated
   • Target: 2.0-2.5 g/kg/day (potentially 180-200 g/day for 80 kg patient)
   • Highest protein requirement scenario in ICU outside burns

2. Energy:

   • 25-30 kcal/kg (avoid overfeeding despite high protein needs)
   • Monitor respiratory quotient (RQ) if indirect calorimetry available
   • Target RQ 0.85-0.95

3. Route:

   • Enteral preferred (maintains gut barrier, reduces bacterial translocation)
   • Post-pyloric feeding often necessary due to gastric dysmotility
   • Parenteral supplementation if enteral intake <60% goal by day 5-7

4. Specialized Formulation:

   • High-protein enteral formula (>20% protein calories)
   • Consider modular protein supplementation (whey protein isolate)
   • Arginine: 15 g/day (wound healing, immune function)
   • Vitamin C: 1-2 g/day
   • Zinc: 30-40 mg/day
   • Vitamin A: 10,000-25,000 IU daily (excessive doses can impair healing; balance needed)

5. Monitoring:

   • 24-hour urine urea nitrogen (calculate nitrogen balance)
   • Target positive nitrogen balance (+4 to +6 g/day)
   • Prealbumin trending
   • Wound measurement and photography with each dressing change

Pearl: Open abdomen protein requirements are second only to major burns. Failure to provide adequate protein (>2 g/kg/day) results in failure of fascial closure, prolonged critical illness, and increased mortality.

Oyster: Watch for abdominal compartment syndrome with aggressive resuscitation and feeding. Intra-abdominal pressure monitoring should continue until definitive fascial closure.

Understanding When Immunonutrition Is Indicated

The Evidence-Based Framework:

Immunonutrition (supplementation with arginine, glutamine, omega-3 fatty acids, and nucleotides) has shown benefit in specific populations but potential harm in others.

PROVEN BENEFIT (Grade A Evidence):

1. Major elective surgery:

   • GI cancer surgery
   • Head and neck cancer surgery
   • Preoperative (5-7 days) and postoperative supplementation
   • Reduces infectious complications by 30-40%[25]

2. Trauma:

   • ISS >18-20
   • Early initiation (<48 hours)
   • Reduced infections and ventilator days[26]

3. Burns:

   • 20% TBSA

   • Arginine and glutamine specifically beneficial
   • Improved wound healing and immune function[14]

POSSIBLE BENEFIT (Grade B Evidence):

• Critically ill surgical patients without severe sepsis
• Mixed ICU populations (heterogeneous data)

NO BENEFIT OR POTENTIAL HARM (Avoid):

1. Severe sepsis/septic shock:

   • REDOXS trial showed harm with glutamine in severe septic shock
   • Meta-analyses mixed but trending toward no benefit[19]

2. Medical ICU patients:

   • Insufficient evidence of benefit
   • Possible increased mortality with glutamine

3. Renal or hepatic failure:

   • Arginine: risk of hyperammonemia in liver failure
   • Glutamine: accumulation in renal failure without RRT

Decision Algorithm:

Patient with large wound/burn in ICU
↓
Is patient in septic shock requiring high-dose vasopressors?
├─ YES → Standard high-protein EN/PN, NO immunonutrition
└─ NO → Continue assessment
    ↓
    Is this trauma, burn >20%, or elective major surgery?
    ├─ YES → Immunonutrition INDICATED
    │        (Arginine 15-20g/day, consider glutamine)
    └─ NO → Medical ICU patient
             ├─ Organ failure (>2 organs)? → NO immunonutrition
             └─ Stable, isolated wound? → CONSIDER immunonutrition

Practical Implementation:

Commercial Immunonutrition Formulas:

• Crucial®: Arginine 14 g/L, omega-3 fatty acids
• Impact®: Arginine 12.5 g/L, omega-3, nucleotides
• Immun-Aid®: Arginine 14 g/L, high branched-chain amino acids

Modular Supplementation Approach:

• Add arginine powder (5 g per scoop) to standard formula: 3-4 scoops/day
• Glutamine dipeptide in TPN: 0.3-0.5 g/kg/day
• Fish oil emulsion (Omegaven®): 0.1-0.2 g/kg/day

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Practical Pearls and Oysters Summary

Pearls:

1. Check albumin, but don't chase it: Albumin is a negative acute phase reactant. Low levels reflect inflammation more than nutritional status. Prealbumin (despite its limitations) changes faster and better reflects nutrition status.

2. The 48-hour rule: Start enteral nutrition within 24-48 hours of ICU admission. Every 12-hour delay increases infectious complications by 30%.

3. Pressure injury = protein deficiency until proven otherwise: Stage 3-4 pressure injuries in ICU patients almost always indicate inadequate protein intake (should be 1.5-2.0 g/kg/day).

4. Indirect calorimetry changes management: Measured energy expenditure often differs from predicted by ±30%. If available, use it.

5. NPWT quantification: Weigh NPWT canisters. Output >100 mL/8-hour collection suggests inadequate protein delivery to wound bed.

Oysters (Pitfalls to Avoid):

1. The overfeeding trap: More calories ≠ better healing. Overfeeding (>30 kcal/kg) worsens hyperglycemia, increases infection risk, and causes hepatic steatosis.

2. Immunonutrition in septic shock: Don't use glutamine or high-dose arginine in septic shock or multiorgan failure. Evidence shows harm.

3. Ignoring micronutrients: Focusing solely on protein/calories while ignoring zinc, vitamin C, and copper dooms wound healing to failure.

4. The "albumin is low, give albumin" mistake: Albumin infusions don't improve wound healing and waste resources. Focus on nutrition substrate delivery, not albumin levels.

5. Forgetting medication effects: Steroids, vasopressors, and propofol all impair wound healing through different mechanisms. Account for this when counseling realistic expectations.

Clinical Hacks:

1. The nitrogen balance quick check: 24-hour UUN (g) + 4 = total nitrogen loss. Compare to nitrogen intake (protein grams ÷ 6.25). Shoot for +4 to +6 g/day positive balance.

2. Zinc deficiency clinical sign: White spots on fingernails (leukonychia) can indicate chronic zinc deficiency—check levels in any patient with refractory wound healing.

3. The vitamin C test: Give 1 g IV vitamin C. If urine turns bright yellow-orange within 2-3 hours, patient is vitamin C replete. If not, they're deficient (crude but sometimes useful bedside test).

4. CRRT micronutrient losses: Double all water-soluble vitamins (B, C) and increase zinc by 50% in patients on CRRT.

5. Prealbumin trending trick: If prealbumin increases by >2 mg/dL per week, nutrition is adequate. Stagnant or declining prealbumin despite feeding suggests ongoing losses or inadequate delivery.

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Conclusion

Wound healing in the ICU represents a complex interplay between disrupted physiology and therapeutic intervention. Critical illness fundamentally alters all three phases of healing through hypercatabolism, persistent inflammation, tissue hypoxia, and medication effects. Success requires more than simply "feeding the patient"—it demands a sophisticated understanding of wound biology, substrate requirements, and strategic use of immunonutrients.

Key principles for optimizing wound healing nutrition in the ICU include:

1. Early aggressive protein delivery (1.5-2.5 g/kg/day depending on wound burden)
2. Adequate but not excessive calories (25-30 kcal/kg)
3. Strategic micronutrient supplementation (zinc, vitamin C, copper, selenium)
4. Selective use of immunonutrition in appropriate populations
5. Continuous monitoring and adjustment based on clinical response

The future of ICU nutrition likely involves personalized approaches guided by metabolomics, continuous bedside metabolic monitoring, and targeted supplementation based on individual deficiencies rather than blanket protocols. Until then, applying the evidence-based principles outlined in this review will optimize outcomes for critically ill patients facing the challenge of wound healing.

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