Efficacy and Safety of High Protein Intake in Critically Ill Patients
Authors: Wei Wu1, Fei Leng2, Minhui Dong1, Jieqiong Song1, Jincheng Zhang1, Fei Han1, Yiqi Qian1, Ming Zhong1
Affiliations:
1Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
2Department of Critical Care Medicine, Shanghai Geriatric Medical Center, Shanghai 201104, China.
Correspondence to: Prof. Ming Zhong, Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
E-Mail: zhong.ming@zs-hospital.sh.cn
DOI: doi.org/10.1097/CM9.0000000000003528
Introduction
Intensive care unit-acquired weakness (ICU-AW) is a severe complication in critically ill patients, often associated with prolonged mechanical ventilation (MV), extended ICU stays, increased hospitalization costs, and higher mortality rates. Current research highlights protein as a crucial substrate for maintaining muscle mass and physical function in critically ill patients, potentially improving clinical outcomes. However, the optimal daily protein intake for these patients remains undetermined, with international guidelines offering inconsistent recommendations ranging from 1.3 g/kg/day to 2.5 g/kg/day for specific patient groups, such as those with obesity.
This study aimed to evaluate the efficacy and safety of high protein intake (2.5–3.0 g/kg/day) in mechanically ventilated critically ill patients, hypothesizing that such an intervention could reverse muscle wasting, reduce ICU-AW incidence, and improve overall prognosis.
Study Design and Methodology
This randomized, double-blinded, positive-controlled, parallel trial was conducted in the surgical ICU of Zhongshan Hospital, Fudan University, between May 2015 and May 2020. The study protocol received approval from the Institutional Ethics Committee of Zhongshan Hospital, Fudan University, in May 2015 (approval No. B 2015–078) and was registered at ClinicalTrials.gov (No. NCT02106624) on April 8, 2014. All participants provided signed informed consent.
Inclusion Criteria: Patients aged 18–75 years admitted to the ICU and receiving MV.
Exclusion Criteria: Expected MV duration of less than 48 hours, physician’s prediction of intolerance to enteral nutrition (EN) or parenteral nutrition (PN), unstable hemodynamics, irreversible critical illness, refusal to participate, severe liver or renal dysfunction, pregnancy, or long-term corticosteroid use.
Participants were randomized into two groups using a computer-generated random number table with a 1:1 allocation ratio. The high protein group received a target protein supply of 2.5–3.0 g/kg/day, with a minimum of 1.5 g/kg/day if high fluid volume was intolerable. The control group received a target protein supply of 1.2–1.5 g/kg/day. Both groups aimed for a calorie intake of 25 kcal/kg/day over seven consecutive days. Nutritional support began within 24 hours of enrollment, with EN as the primary protein source. Additional protein was supplemented via PN if necessary.
Outcomes and Measurements
Primary Outcomes: 90-day and 28-day survival rates after enrollment.
Secondary Outcomes: Incidence of ventilator-associated pneumonia (VAP), catheter-associated infections, ventilation-free days, ICU length of stay, and total hospitalization duration. Nutritional indicators were also assessed.
Data analysis was performed using SPSS 22.0, GraphPad Prism 7.0, and R 3.6.3. Categorical variables were compared using the chi-square test, while continuous data were analyzed using the Student’s t-test or Mann–Whitney U test, depending on distribution normality. A P-value <0.05 was considered statistically significant.
Results
A total of 91 participants (42 in the high protein group and 49 in the control group) were included in the final analysis. Baseline characteristics, including age, sex, body mass index (BMI), Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, modified Nutrition Risk in Critically Ill (mNUTRIC) score, diagnosis at ICU admission, and comorbidities, were similar between the two groups.
Primary Outcomes:
- 90-day survival rates: 78.6% (33/42) in the high protein group vs. 69.4% (34/49) in the control group (odds ratio [OR], 1.621; 95% confidence interval [CI], 0.621–4.202; P = 0.350).
- 28-day survival rates: 80.9% (34/42) in the high protein group vs. 77.6% (38/49) in the control group (OR, 1.232; 95% CI, 0.442–3.423; P = 0.798).
Secondary Outcomes:
- VAP incidence: Significantly lower in the high protein group (4.8% [2/42]) compared to the control group (20.4% [10/49]) (OR, 0.201; 95% CI, 0.041–0.952; P = 0.033).
- No significant differences were observed in catheter-associated infections, ventilation-free days, ICU length of stay, or hospital length of stay.
Nutritional Indicators:
- Daily protein intake: Higher in the high protein group (1.76 ± 0.68 g/kg/day) vs. the control group (1.28 ± 0.30 g/kg/day) (P < 0.001).
- Protein delivered via EN: Higher in the high protein group (0.42 ± 0.40 g/kg/day) vs. the control group (0.25 ± 0.34 g/kg/day) (P = 0.03).
- Protein delivered via PN: Higher in the high protein group (1.32 ± 0.70 g/kg/day) vs. the control group (0.94 ± 0.47 g/kg/day) (P = 0.04).
Subgroup Analysis:
- High protein intake showed survival benefits only in patients with prolonged ICU stays (>7 days):
- 90-day survival rate: 90.3% (28/31) in the high protein group vs. 66.7% (30/45) in the control group (P = 0.01).
- 28-day survival rate: 90.3% (28/31) in the high protein group vs. 75.5% (34/45) in the control group (P = 0.04).
Adverse Effects:
- Hyperglycemia: Comparable incidence between the high protein group (38.1%) and the control group (44.9%) (P = 0.53).
- Gastric retention: Comparable incidence between the high protein group (4.8%) and the control group (10.2%) (P = 0.45).
- No serious adverse events were reported.
Discussion
This study found that early high protein support did not improve 90-day or 28-day survival rates for critically ill patients overall. However, it significantly improved survival rates in patients with prolonged ICU stays (>7 days). This suggests that protein supplementation may reduce muscle protein breakdown, promote early activity, and enhance survival in this subgroup.
The lower incidence of VAP in the high protein group supports the hypothesis that high protein nutritional support inhibits ICU-AW by promoting muscle recovery, thereby improving expectoration and early mobilization, which can prevent aspiration-induced pneumonia. Additionally, high protein intake may enhance the immune response against infections in ICU patients.
Limitations of this study include its single-center design, relatively small sample size, and low compliance rate for protein intake due to gastrointestinal intolerance. Despite these limitations, the actual protein intake in the high protein group remained above 1.5 g/kg/day, which is higher than in previous studies.
Conclusion
High protein feeding does not improve the 90-day and 28-day survival rates of critically ill patients receiving MV overall. However, it significantly improves survival rates in patients with prolonged ICU stays (>7 days) and reduces the incidence of VAP. These findings highlight the potential benefits of high protein nutritional support in specific subgroups of critically ill patients.
Conflicts of Interest: None.
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How to Cite This Article: Wu W, Leng F, Dong MH, Song JQ, Zhang JC, Han F, Qian YQ, Zhong M. Efficacy and safety of high protein intake in critically ill patients. Chin Med J 2025;138:880–882. doi.org/10.1097/CM9.0000000000003528
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