Why this article matters
Critical illness triggers a profound, highly coordinated metabolic stress response that extends far beyond “hypercatabolism.” This comprehensive review reframes how we understand energy metabolism, nutrition, endocrine signaling, immune function, and recovery across the acute, subacute, and chronic phases of critical illness. Importantly, it challenges long-standing assumptions around “early full feeding” and high-protein strategies, advocating instead for phase-appropriate, physiology-aligned metabolic care.
Key concepts you need to know
1. The metabolic response to stress is phasic, not static
The authors describe three overlapping phases:
- Acute phase: Sympathetic activation, cortisol dominance, insulin resistance, and rapid catabolism
- Subacute phase: Persistent inflammation, mitochondrial dysfunction, anabolic resistance
- Chronic phase / recovery: Either transition toward anabolic repair or progression to chronic critical illness (CCI) and PICS
Failure to recognize these phases leads to mistimed nutrition and iatrogenic harm.
2. Early catabolism is adaptive — forcing anabolism may be harmful
During early critical illness, endogenous energy production remains high and cannot be fully suppressed by feeding. Excess early calories or protein:
- Inhibit autophagy
- Worsen mitochondrial dysfunction
- Increase lipotoxicity and oxidative stress
This explains why trials supporting early full feeding or high protein have largely failed to improve outcomes.
3. Mitochondrial dysfunction is central to metabolic failure
Critical illness shifts energy production away from efficient β-oxidation toward:
- Glycolysis
- Lactate utilization
- Ketone metabolism
Markers such as N-formylmethionine, acylcarnitines, and lactate reflect impaired oxidative phosphorylation. Inadequate autophagy allows damaged mitochondria to accumulate, directly linking metabolic failure to mortality.
4. Lactate and ketones are not “waste products”
The review reframes lactate as a key alternative fuel and signaling molecule (“lactormone”), supporting:
- Brain, immune, and renal metabolism
- Immune modulation and inflammation resolution
Similarly, β-hydroxybutyrate activates protective pathways, including autophagy, mitochondrial biogenesis, and inflammasome suppression — highlighting why aggressive glucose-centric thinking is outdated.
5. Stress hyperglycaemia is context-dependent
Early insulin resistance is adaptive, redirecting glucose to vital organs. However:
- Persistent insulin resistance becomes maladaptive
- Tight glycaemic control offers no mortality benefit and increases hypoglycaemia
Current evidence supports moderate glucose targets (140–200 mg/dL) rather than aggressive normalization.
6. High-protein strategies fail to improve outcomes — and may cause harm
Across multiple RCTs and meta-analyses:
- Higher protein intake does not improve survival, ventilator days, or functional recovery
- Potential harm is seen in patients with acute kidney injury
- Anabolic resistance limits effective protein utilization
The message is clear: more protein is not better, especially early.
7. Chronic critical illness reflects failed metabolic resolution
Some patients transition to persistent inflammation, immunosuppression, and catabolism (PICS), characterized by:
- Ongoing muscle wasting
- Immune dysfunction
- Endocrine suppression
- Long-term disability
This reinforces the need for biomarkers and metabolomics to identify when patients are ready for anabolic strategies.
Clinical takeaways for ICU practice
- 🔹 Early phase: Permissive underfeeding (≈50–70% EE), trophic enteral nutrition
- 🔹 Avoid early high-protein dosing
- 🔹 Use indirect calorimetry when available
- 🔹 Moderate glycaemic control over tight targets
- 🔹 Recognize metabolic phase before escalating nutrition
- 🔹 Future direction: metabolic endotyping to personalize care
Bottom line
This review marks a paradigm shift in critical care metabolism. The goal is no longer to “replace what is lost” immediately, but to support adaptive stress responses early, protect mitochondria, preserve autophagy, and time anabolic support correctly. Precision metabolic care — not blanket nutrition targets — represents the future of ICU practice.
As always, thank you for being part of the One Article a Day Challenge. Your continued engagement is what drives evidence-based critical care forward.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
