Efficacy and safety of high protein intake in critically ill patients

To the Editor: Intensive care unit-acquired weakness (ICU-AW) is a serious complication in critically ill patients, associated with prolonged mechanical ventilation (MV), extended ICU stays, increased hospitalization costs, and higher mortality rates. Current research suggests that protein may be the most crucial substrate for maintaining muscle mass and physical function in critically ill patients and improving clinical outcomes.[1] However, the optimal daily protein intake for critically ill patients remains undetermined. International guidelines for high protein intake are inconsistent, recommending either 1.3 g·kg−1·day−1 or a range of 1.2–2.0 g·kg−1·day−1.[2,3] For special patient groups, such as those with obesity, even higher protein doses (2.0–2.5 g·kg−1·day−1) are recommended.[1] We hypothesized that high protein feeding (2.5–3.0 g·kg−1·day−1) in critically ill patients may reverse muscle wasting, reduce the incidence of ICU-AW, and improve overall prognosis. Therefore, this study aimed to evaluate the efficacy and safety of high protein intake in mechanically ventilated critically ill patients. This was a randomized, double-blinded, positive-controlled, parallel trial conducted in the surgical ICU of Zhongshan Hospital, Fudan University, between May 2015 and May 2020. The study protocol was approved by the Institutional Ethics Committee, Zhongshan Hospital, Fudan University, in May 2015 (apporval No. B 2015–078). The trial was registered at ClinicalTrials.gov (No. NCT02106624) on April 8, 2014. All the patients were enrolled upon signed informed consent. The inclusion criteria included patients aged 18 years to 75 years who were admitted to the ICU and received MV. The exclusion criteria included an expected MV duration of less than 48 h, physician’s prediction of patients’ intolerance to enteral nutrition (EN) (e.g., bowel perforation, ischemic intestinal necrosis, anastomotic fistula) or parenteral nutrition (PN), unstable hemodynamics, irreversible critical illness, refusal to participate in the trial, severe liver dysfunction, severe renal dysfunction, pregnancy, or long-term use of corticosteroid treatment. Randomization was performed according to a computer-generated random number table with an allocation rate of 1:1. The computer-generated random assignment sequence was concealed in opaque envelopes. Patients were randomly assigned to the high protein group, in which patients were provided with a target protein supply of 2.5–3.0 g·kg−1·day−1 and no less than 1.5 g·kg−1·day−1 if patients could not tolerate the high fluid volume containing targeted protein. The nutritional support program was started and continued for the next 7 consecutive days. Patients in the control group received a target protein supply of 1.2–1.5 g·kg−1·day−1. Both groups received a similar calorie intake, with a target of 25 kcal·kg−1·day−1 for the next 7 consecutive days. Nutritional support began within 24 h of enrollment. EN was preferred as the primary protein source. To meet the protein target, additional proteins were supplemented via PN. The primary outcome was the 90-day and 28-day survival rate after enrollment. The secondary outcomes included ventilator-associated pneumonia (VAP), catheter-associated infection, ventilation-free days, length of ICU stay, and total hospitalization duration. Nutritional indicators were also assessed. Categorical variables were compared between the two groups using the chi-square test. Continuous data were reported as the mean and standard deviation (SD). Medians and interquartile ranges (IQRs) were analyzed using the Student’s t-test for normally distributed data and the Mann–Whitney U test for non-normally distributed data. Data were analyzed using SPSS 22.0 (IBM, Armonk, NY, USA), GraphPad Prism 7.0 (La Jolla, CA, USA), and R 3.6.3 (Waltham, MA, USA). A P value <0.05 was considered statistically significant. Patients were recruited from May 2015 to May 2020, and a total of 91 participants (42 in the high protein group and 49 in the control group) were included in the final analysis of the outcomes [Supplementary Figure 1, https://links.lww.com/CM9/C356]. The basic characteristics of both groups are presented in Supplementary Table 1, https://links.lww.com/CM9/C356. The 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 [Supplementary Table 1, https://links.lww.com/CM9/C356]. The 90-day survival rates were not significantly different between the two groups, which were 78.6% (33 of 42) in the high protein group and 69.4% (34 of 49) in the control group (odds ratio [OR], 1.621, 95% confidence interval [CI], 0.621–4.202, P = 0.350) [Supplementary Table 2, https://links.lww.com/CM9/C356]. The 28-day survival rate was 80.9% (34 of 42) in the high protein group and 77.6% (38 of 49) in the control group (OR, 1.232, 95% CI, 0.442–3.423, P = 0.798) [Supplementary Table 2, https://links.lww.com/CM9/C356]. The overall survival was also comparable between the two groups, whether for the 90-day survival or the 28-day survival [Figure 1A, B]. Comparisons of the secondary outcomes are listed in Supplementary Table 2, https://links.lww.com/CM9/C356. The incidence rate of VAP in the high protein group was significantly lower than that in the control group (4.8% [2 of 42] vs. 20.4% [10 of 49], OR, 0.201, 95% CI, 0.041–0.952, P = 0.033), while no significant differences were identified in the incidence rate of catheter-associated infections, ventilation-free days, ICU length of stay, or hospital length of stay [Supplementary Table 2, https://links.lww.com/CM9/C356].Figure 1: Kaplan-Meier survival analysis of critically ill patients receiving high-protein group vs. control group. (A) Kaplan–Meier estimates of 90-day survival probabilities for patients in the high protein and control groups (P = 0.97); (B) Kaplan–Meier estimates of 28-day survival rates for patients in the high protein and control groups (P = 0.70); (C) Survival curves of patients with prolonged ICU stays in the high protein group and control group 90 days after enrollment (P = 0.008); (D) Survival curves of patients with prolonged ICU stays in both groups following 28 days after enrollment (P = 0.04). CI: Confidence interval; HR: Hazard ratio; ICU: Intensive care unit.The daily protein intake (1.76 ± 0.68 g·kg−1·day−1) of the high protein group was higher than that (1.28 ± 0.30 g·kg−1·day−1) of the control group (P <0.001). In the high protein group, the amount of protein delivered via the enteral route was 0.42 ± 0.40 g·kg-1·day-1, which was significantly higher than the 0.25 ± 0.34 g·kg-1·day-1 in the control group (P = 0.03). Similarly, the amount of protein delivered via the parenteral route was 1.32 ± 0.70 g·kg-1·day-1, also significantly higher than the 0.94 ± 0.47 g·kg-1·day-1 in the control group (P = 0.04)[Supplementary Table 3, https://links.lww.com/CM9/C356]. The distribution of protein intake and energy intake levels is shown in Supplementary Figure 2 and 3, https://links.lww.com/CM9/C356. As for the daily calorie intake, neither EN nor PN showed significant differences between the two groups [Supplementary Table 3, https://links.lww.com/CM9/C356]. Comparing the high protein group and the control group, no statistically significant differences were identified in the nutrition-related parameters, liver function, renal function, continuous renal replacement therapy (CRRT) administration and electrolyte levels, or midpoint musculus rectus femoris cross-sectional area (CSA) values between day 0 and day 7 after enrollment [Supplementary Table 4, https://links.lww.com/CM9/C356]. The subgroup analysis of the 90-day survival rate is elucidated in Supplementary Figure 4, https://links.lww.com/CM9/C356. Among all the evaluated subgroups, high protein intake showed benefits only in patients with prolonged ICU stay (>7 days) (hazards ratio [HR], 0.21, 95% CI, 0.06–0.82, P = 0.02). In addition, survival analysis also found that in patients with prolonged ICU stay, the high protein group showed improved overall survival rates compared to the control group, with both a higher 90-day survival rate (90.3% [28 of 31] vs. 66.7% [30 of 45], P = 0.008) and a higher 28-day survival rate (90.3% [28 of 31] vs. 75.5% [34 of 45], P = 0.04) [Figure 1C,D]. The major adverse effects observed in this study included dysglycemia and gastric retention. The incidence of hyperglycemia in the high protein group and the control group was comparable (38.1% vs. 44.9%, P = 0.53), as was the incidence of gastric retention (4.8% vs. 10.2%, P = 0.45). No serious adverse events or suspected unexpected serious complications were observed during the study period. In the prospective randomized controlled trial of mechanically ventilated patients admitted to the ICU, we found that early high protein support did not improve 90-day or 28-day survival rates for critically ill patients in the ICU. Interestingly, we observed that high protein intake improved 90-day and 28-day survival rates in patients with prolonged ICU stays (>7 days). We speculate that protein supplementation might reduce muscle protein breakdown, promote early activity, and be associated with improved survival rates in patients with prolonged ICU stays. On the contrary, critically ill patients admitted to the ICU for less than 7 days tend to be either transferred out of the ICU early in a mild condition or extremely critical, which leads to death, so we hypothesize that high protein intake is less likely to improve the survival rate in this situation. Additionally, secondary outcome analysis revealed a lower incidence of VAP in patients in the high protein group. It is reasonable to speculate that high protein nutritional support inhibits ICU-AW in critically ill patients by promoting muscle recovery,[4] which consequently contributes to promoting expectoration and even early mobilization, thus preventing aspiration-induced pneumonia. Moreover, high protein nutritional support may enhance the defensive immune response against infections in ICU patients. Our study has several limitations that need to be addressed. First, this was a single-center study with a relatively small sample size, which may limit the generalizability of our conclusions. Second, the low compliance rate for protein intake might have impact on the study outcomes. This may be attributed to gastrointestinal intolerance induced by EN (the primary preferred route for protein supplementation). However, the actual protein intake was not <1.5 g·kg−1·day−1, which is still higher than in previous studies, such as those with a protein intake of 1.0–1.5 g·kg−1·day−1.[5] High protein feeding does not improve the 90-day and 28-day survival rates of critically ill patients receiving MV, but it improves the 90-day and 28-day survival rates in patients with prolonged ICU stays (>7 days) in the prospective randomized controlled trial. High protein nutritional support can also reduce the incidence of VAP. Conflicts of interest None.