In-Bed Cycling Plus Protein Supplementation Fails to Improve Physical Recovery in ICU Patients with Acute Respiratory Failure, NEXIS Trial Finds
核心洞察
The NEXIS trial found that combining daily in-bed cycling with intravenous amino acid supplementation did not significantly improve 6-minute walk distance at hospital discharge compared to usual care alone in ICU patients with acute respiratory failure (搜索).
At discharge, median 6MWD was 108 meters in the intervention group versus 95 meters in the control group, with no significant differences in quadriceps force, grip strength, or other physical function measures.
Researchers recommend against higher protein intake during the acute phase of critical illness, consistent with three prior large randomized trials showing no benefit and potential harm.
A multicenter randomized phase 2 trial has found that adding daily in-bed cycling and intravenous amino acid supplementation to usual care does not improve physical recovery at hospital discharge for patients with acute respiratory failure (搜索) (ARF) in the intensive care unit (ICU). The findings, published in the American Journal of Respiratory and Critical Care Medicine, challenge the hypothesis that combining exercise with enhanced protein intake—a strategy proven effective in frail and elderly populations—would similarly benefit critically ill patients.
The Nutrition and Exercise in Critical Illness (NEXIS) trial enrolled 115 ICU patients with acute respiratory failure (搜索) across nine U.S. academic medical centers. Of these, 104 were mechanically ventilated. Patients were randomized to receive either protocolized in-bed cycling for 45 minutes per day plus intravenous amino acid (targeting a total daily protein intake of 2 g/kg–2.5 g/kg) on top of usual care, or usual care alone.
No Significant Difference in Primary Endpoint
At hospital discharge, the primary outcome—6-minute walk distance (6MWD)—showed a median of 108 meters in the intervention group compared with 95 meters in the control group, a difference that did not reach statistical significance. Secondary outcomes similarly showed no meaningful separation between groups, including quadriceps force, grip strength, functional status score for the ICU, short physical performance battery, length of mechanical ventilation, reintubation rates, ICU readmission, and discharge location.
“Based on the findings of this study and on three prior large, randomized trials evaluating protein supplementation (without added exercise), higher protein intake (with or without added exercise) should not be used in the acute phase of critical illness,” said Dale M. Needham, MD, PhD, professor of pulmonary and critical care medicine and physical medicine and rehabilitation at the Johns Hopkins University School of Medicine.
The average time from ICU admission to randomization was 61 hours in both groups. Patients in the intervention arm cycled for an average of 40 minutes (approximately 2 miles) per day and achieved an average daily protein intake of 1.9 g/kg—roughly twice that of the control group.
Six-Month Follow-Up Confirms No Long-Term Benefit
Six-month follow-up data were available for 89 surviving patients. The two groups remained comparable across multiple domains, including Short-Form-36v2 quality of life scores, EQ-5D-5L health state and index scores, activities of daily living (Katz and Lawton scales), Hospital Anxiety Depression Scale scores, PTSD-related Impact of Event Scale-Revised scores, and Montreal Cognitive Assessment scores. Employment status and health care utilization also did not significantly differ between groups.
Safety Considerations
In-hospital mortality was similar between the intervention and control groups (12% vs. 13%). However, eight serious adverse events occurred in the intervention group compared with three in the control group. Events of interest included phlebitis or extravasation (four cases in the intervention group vs. one in the control group) and azotemia (two vs. zero).
Anabolic Resistance as a Likely Explanation
Needham suggested that anabolic resistance—a biological phenomenon limiting the body's ability to effectively use supplemental protein during the early stages of critical illness—may explain the lack of benefit. “When they're sick and on life support, there is an imbalance of increased protein breakdown and decreased protein synthesis, so patients are having a net loss of protein,” Needham explained. Yet providing extra protein does not appear to overcome this resistance in the acute phase.
The trial was originally designed to enroll 128 patients, but enrollment was paused during the COVID-19 pandemic and grant funding ended in 2025 before the target was reached. Additionally, after three large protein-only trials suggested potential harm in patients with acute kidney injury (搜索), such patients were excluded from NEXIS, further reducing the eligible population.
Early Mobilization Remains Foundational
Despite the negative result for protein supplementation, the broader evidence base—encompassing more than 150 randomized controlled trials—continues to support early mobilization as safe and beneficial for ARF patients in the ICU. Needham noted that the control group in NEXIS received usual care rehabilitation at a higher frequency than is typical in many U.S. ICUs, which may have attenuated the ability to detect a benefit from the cycling intervention alone.
“I always think about exercise and rehab like a drug ... [with an] optimal therapeutic window where the dose is neither too low to provide improvement nor too high and causes adverse side effects,” said Stephanie Hiser, PhD, a physical therapist at Johns Hopkins Hospital and co-investigator on the trial.
Future Research Priorities
Needham emphasized that future investigation should focus on understanding whether and when anabolic resistance decreases sufficiently—later in critical illness or during the recovery period—for protein supplementation combined with exercise to enhance outcomes. “Priorities for future investigation include addressing anabolic resistance... and better understanding individual patients' differences in recovery,” he said.
The research team also aims to determine optimal dosing thresholds for rehabilitation interventions, particularly in settings where physical therapists are scarce resources. “When rehabilitation therapists are scarce resources in the ICU, as they typically are, more patients are helped by knowing the threshold where more therapy stops speeding up recovery,” Needham said.
The findings underscore the persistent challenge of post-ICU muscle weakness. “Consistent with prior studies by our group and by other investigators, the NEXIS trial noted that substantial physical impairment was common among patients in both study groups,” Needham told Healio. “This finding underscores the continued need for innovative solutions to help ICU survivors regain strength and physical function after discharge.”