Review for 10.1186/s12876-025-04122-4 (2025)

Title: Analysis of influencing factors and nursing strategies for enteral nutrition patients
complicated with refeeding syndrome in ICU
Version: 2 Date: 11 May 2025
Reviewer's report:
This revised manuscript is much improved in scope and detail, offering a clearer background and
methodology. The introduction now provides a solid definition of refeeding syndrome (RS) and
outlines its mechanisms  . The authors have also added important context about the ICU setting
– for example, how critical illness, medications, and metabolic stress increase RS risk . These
additions make the paper more accessible to readers unfamiliar with RS. One minor suggestion:
ensure consistency in terminology (sometimes “re-feeding” is hyphenated, elsewhere not). Also,
Figure 1 (flowchart) could be edited for consistency (use “refeeding” as one word). Such minor
language edits would polish the clarity further.
Study Design: The study design is a single-center retrospective analysis of 173 ICU patients
receiving enteral nutrition (EN) in 2020–2021, divided into a non-RS control group and an RS
group. This design is appropriate for exploring associations (risk factors) but inherently limited
in establishing causation. The retrospective nature was acknowledged as a limitation. A strength
is that inclusion/exclusion criteria are clearly defined and the groups were well-characterized
(Table 1 and 2). The sample size (n=173 with 45 RS cases) is reasonable, though still on the lower
side for multivariate analysis with many variables. The authors correctly note that the results may
not be broadly generalizable due to the single-center, relatively small sample . A major design
concern is the lack of a prospective control for the intervention: all RS patients received the
“targeted nursing strategies,” and there was no comparison group of RS patients without these
measures. This makes it difficult to definitively attribute patients’ laboratory improvements to
the interventions (as opposed to spontaneous recovery or standard ICU care). The authors do
propose future prospective studies to verify the intervention’s impact , which is appropriate.
Novelty and Clinical Relevance: Identifying risk factors for refeeding syndrome in ICU enteral
feeding is a pertinent clinical topic. While RS is well-known in malnutrition and refeeding
contexts, its incidence and predictors in critically ill EN patients have been less certain. The
findings that rapid feeding rate, high protein load, and warmed feeding solutions are associated
with RS risk add new angles to the existing knowledge (most prior focus has been on calorie/
carbohydrate load and patient comorbidity) . These results highlight practical factors that ICU
staff can modify – for instance, feeding speed >50 ml/h had an OR ~3.8 for RS , and protein
#1.2 g/kg had an OR ~5.5 . Such findings are clinically relevant because they suggest that more
cautious feeding (slower rates, moderated protein initially) could reduce RS occurrence. The
study’s novelty is moderate – some risk factors like age, high NRS-2002 score, and mechanical
ventilation (indicating severe illness) confirm what one would expect , and similar associations
have been reported in previous RS literature. However, the emphasis on nutritional management
factors (rate, protein, temperature) is a valuable contribution that could inform ICU nutritional
protocols.
Methodological Details and Validity: The methodology is now described with commendable
detail. The authors defined RS clearly (including mild/moderate/severe criteria) # and ensured
all patients were assessed under those criteria. They also recorded a wide range of variables:
demographics, comorbidities, APACHE II and NRS-2002 scores, and detailed enteral nutrition
parameters . The thoroughness of data collection strengthens the analysis. One point of potential
bias is that the study did not include any long-term outcomes; as noted, they did not follow
patients after ICU discharge . We therefore do not know if those who had RS or certain risk
factors fared worse later, which limits the clinical impact slightly. Another point is that because
this was an observational retrospective study, confounding factors could affect the results.
The authors did well to discuss some confounders in depth – for example, use of diuretics
causing electrolyte loss, or diabetes and cardiac conditions influencing RS risk . Most of these
were not measured as variables in their regression (they note comorbidities qualitatively but
did not include specific medications in the model). It’s good that they acknowledge these
unmeasured confounders . One important confounder inherent in their analysis is that the sickest,
malnourished patients might have received more aggressive nutrition (e.g. higher protein or
faster feeding to meet goals), which in turn predisposed them to RS – cause and effect can
be circular. The logistic regression attempted to adjust for illness severity (APACHE II) and
malnutrition risk (NRS-2002), which lends credibility to the identified independent risk factors.
The statistical methods are standard and mostly sound. Baseline comparisons used #² and t-tests
appropriately, and multivariate logistic regression identified independent predictors (seven were
significant) . One suggestion: in reporting the logistic results, providing the odds ratios with
confidence intervals in the text would enhance transparency. Currently, the key results are stated
(which factors were significant) , but readers must consult Table 4 for ORs. Also, it appears the
NRS-2002 score was treated as ordinal (0,1,2) in the model; it might have been clearer to split
it into two dummy categories (moderate risk vs high risk) to see which level drives risk. These
are minor statistical presentation details and do not undermine the overall validity. The results
section is concise and factual, and the data in tables support the conclusions drawn.
Figures and Tables: The tables are generally well-organized and informative. Table 1 and 2
together cover baseline patient characteristics and feeding-related factors, showing significant
differences that led to the risk factor analysis. As mentioned, Table 2 includes new data on energy
and mineral intake – it would be helpful to indicate whether those differences are significant or
not (currently it looks incomplete). Table 3 and 4 present the regression analysis clearly, with
Table 3 defining how each variable was coded . One issue is that Table 4’s formatting led to
some confusion: for example, the 95% CI for diabetes (X1) appears as “1.856–4.151” which
contradicts its p=0.104 (likely a formatting error, since a CI spanning 1 would be expected) – the
authors should double-check the CIs for consistency (they likely meant 0.856–4.151) to avoid
confusion. Figure 1 (flowchart) is a helpful visual of the study design. It confirms that all 173
patients were analyzed in two groups, and outlines the data collection steps. The text inside the
boxes could be proofread (for instance, “no re feeding syndrome” should read “no refeeding
syndrome”), but the diagram’s content is understandable. Figure 2 is a strength of the paper
– it graphically illustrates the effect of the nursing intervention on the RS patients’ nutritional
markers. The before-and-after scatter plots for phosphorus, potassium, magnesium, albumin, and
prealbumin show clear improvements with highly significant differences (p<0.01 or p<0.001)
# #. This figure adds impact by demonstrating that nearly every patient had an upward trend
in these values (the cloud of red “after” points is visibly higher than the blue “before” for each
nutrient). The figure is properly labeled in the caption . In summary, the tables and figures are
adequate in conveying the results, with just minor tweaks needed for complete clarity.
Interpretation and Discussion Quality: The discussion has been significantly expanded and
is now one of the manuscript’s strong points. The authors not only compare their findings
with prior studies but also delve into the mechanisms behind them. They provide a detailed
pathophysiological explanation of why, for example, rapid feeding and high carbohydrate/
protein intake precipitate electrolyte shifts and thiamine depletion . They cite relevant literature
to support these mechanisms (e.g., references on insulin secretion and electrolyte uptake,
thiamine’s role in metabolism) . This helps readers understand why the identified factors matter.
The discussion also smartly addresses each major risk factor: age and high NRS (malnutrition
risk) leading to vulnerability , severity of illness (APACHE II) and mechanical ventilation
reflecting patients who are already in catabolic states #, and the modifiable feeding practices
(speed, protein load, temperature) that can exacerbate the metabolic imbalance . For each, the
authors provide citations or logical reasoning, which lends credibility to their interpretations.
They have also added a paragraph on the clinical significance of their work #. They argue that
knowing these risk factors allows ICU staff to intervene earlier – for instance, by identifying
high-risk patients on admission and adjusting feeding plans accordingly. This is a sound
conclusion, although as noted, the manuscript stops short of demonstrating early intervention
prevents RS (that remains an implication). The limitations section is frank and comprehensive.
The authors list the key limitations: retrospective design with possible information bias, no long-
term follow-up, small sample, and not examining types of comorbidities in detail . They even
acknowledge that they did not construct a predictive model and that the long-term prognosis
impact is unclear #. This transparent discussion of limitations aligns with the reviewers’ requests
and shows the authors understand the study’s boundaries. One additional limitation to consider
is that all patients who developed RS were treated – so we cannot know what their outcomes
would have been without treatment. However, ethically and clinically it’s obvious they had to be
treated, so this is not truly a critique, just an inherent study design fact. The authors’ suggestions
for future research (larger prospective studies, incorporation of comorbidity factors, building a
risk prediction model) are appropriate and flow naturally from their findings .
Strengths and Weaknesses Summary: In sum, the manuscript’s strengths lie in its thorough data
reporting after revision and its detailed discussion. It addresses an important ICU complication
with practical implications. The main weaknesses are those common to retrospective analyses:
potential unseen confounders and an inability to prove causation or the effectiveness of
interventions. The authors have mitigated these by multivariate analysis and by candidly
acknowledging what the study cannot prove. A remaining weakness is that some outcomes are
surrogate (lab values) rather than clinical endpoints – we know electrolytes improved, but not
whether, say, ICU stay was shortened or mortality reduced. Given this is a focused exploratory
study, such outcomes might be beyond its scope, but they are worth noting as next steps.
From a peer-review perspective, the revised manuscript largely satisfies the prior concerns and
is close to publishable quality. I recommend a final round of minor revisions to address the subtle
issues above (clarifying any data presentation ambiguities and polishing language). The study’s
conclusions about risk factors are well-supported by the data  , and the emphasis on proactive
nutritional management is valuable for critical care practice. With small edits, this paper will be
a solid contribution to BMC Gastroenterology, informing clinicians about how to recognize and
mitigate refeeding syndrome in high-risk enterally-fed patients.