Impact of protein intervention timings on critically ill patients: A systematic review and meta- analysis

Pranav Kumar Sharma1, Sanjiya Arora2, Tirth Bhavsar3, Mamta Kamboj4, Rahul Kamboj5, Varnika Gupta6, Anitha Sigamani Ramamurthi7, Kumari Uthayakumar8, Ajay Singh9, Sachin Mahendrakumar Chaudhary10, Arghadip Das11, Arianisa Bajrami12, Sumesh Singh13, Devendra Tripathi14

1 Department of Internal Medicine, Lake Cumberland Regional Hospital, Somerset, Kentucky, USA
2 Department of Internal Medicine, Rohilkhand Medical College, Bareilly, Uttar Pradesh, India
3 Department of Internal Medicine, Smt. NHL Municipal Medical College, Ahmedabad, Gujarat, India
4 Department of Internal Medicine, Government Medical College, Patiala, Punjab, India
5 Department of Internal Medicine, King George’s Medical College, Lucknow, Uttar Pradesh, India
6 Department of Internal Medicine, Lala Lajpat Rai Memorial Medical College, Uttar Pradesh, India
7 Department of Internal Medicine, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India
8 Department of Internal medicine, Nanjing Medical University, Nanjing, China
9 Department of Internal Medicine, Sri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh, India
10 Department of Internal Medicine, Gujarat Cancer Society Medical College, Hospital and Research Center, Ahmedabad, Gujarat, India
11 Department of Internal Medicine, Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India
12 Department of Internal Medicine, University of Tirana, Albania
13 Department of Internal Medicine, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
14 Department of Internal Medicine, Nazareth Hospital, Philadelphia, PA. USA

DOI: 10.2478/jccm-2025-0047

Background: Critically ill patients experience metabolic alterations that promote muscle atrophy and protein catabolism, increasing morbidity and mortality. While adequate protein provision is essential, the optimal timing remains controversial. Guidelines recommend higher protein targets, but evidence from randomized controlled trials is limited and inconsistent.
Aim: To evaluate the effects of early versus late protein supplementation on mortality, complications, and clinical outcomes in critically ill patients.
Methods: A systematic review and meta-analysis were conducted using PubMed, Embase, Cochrane Library, and Google Scholar (January 2010–December 2022). Studies comparing early and late protein administration in adult ICU patients were included. Primary outcomes were mortality, infectious complications, overall complications, pneumonia, ICU/hospital length of stay, and mechanical ventilation duration.
Results: Thirteen studies (8 RCTs, 3 retrospective, 2 prospective cohorts) involving 10,672 patients were analyzed. Mortality (RR = 0.87, 95% CI: 0.74–1.04, p = 0.11; I² = 36%), overall complications (RR = 0.87, 95% CI: 0.74–1.02, p = 0.08; I² = 26%), infectious complications (RR = 0.86, 95% CI: 0.58–1.27, p = 0.37; I² = 65%), and pneumonia (RR = 0.78, 95% CI: 0.41–1.48, p = 0.34; I² = 0%) showed no significant differences between early protein (EP) and late protein (LP) groups. EP significantly reduced ICU length of stay (MD = –0.28 days, 95% CI: –0.33 to –0.23, p < 0.00001; I² = 99%) and mechanical ventilation duration (MD = –0.66 days, 95% CI: –0.90 to –0.41, p < 0.00001; I² = 85%), but was associated with a longer hospital stay (MD = 0.47 days, 95% CI: 0.31–0.63, p < 0.00001; I² = 98%).
Conclusion: Early protein supplementation does not significantly affect mortality or major complications but may shorten ICU stay and ventilation duration. High heterogeneity for some outcomes warrants cautious interpretation.

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