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Incidence and Outcome of Refeeding Syndrome in Neurocritically Ill Patients

Ruiqi Xiong, Hua Huang, Yongming Wu, Shengnan Wang, Dongmei Wang, Zhong Ji,
Zhenzhou Lin, Nailiang Zang, Suyue Pan, Kaibin Huang

PII: S0261-5614(20)30356-3
DOI: https://doi.org/10.1016/j.clnu.2020.06.038
Reference: YCLNU 4370

To appear in: Clinical Nutrition

Received Date: 13 February 2020

Revised Date: 17 April 2020
Accepted Date: 29 June 2020

Please cite this article as: Xiong R, Huang H, Wu Y, Wang S, Wang D, Ji Z, Lin Z, Zang N, Pan S,
Huang K, Incidence and Outcome of Refeeding Syndrome in Neurocritically Ill Patients, Clinical
Nutrition, https://doi.org/10.1016/j.clnu.2020.06.038.

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© 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Title: Incidence and Outcome of Refeeding Syndrome in Neurocritically Ill Patients

Authors: Ruiqi Xiong a, #, Hua Huang a, b, #, Yongming Wu a, Shengnan Wang a,

Dongmei Wang a, Zhong Ji a, Zhenzhou Lin a, Nailiang Zang a, Suyue Pan a, *, Kaibin
Huang a, *

#
These two authors contributed equally to this study.

Affiliations: a Department of Neurology, Nanfang Hospital, Southern Medical University,

Guangzhou, China

b
Department of Neurology, Shenzhen People’s Hospital, Southern Medical University,
Guangzhou, China

*Corresponding authors: Kaibin Huang (E-mail: hkb@smu.edu.cn) and Suyue Pan

(E-mail: pansuyue@smu.edu.cn), Department of Neurology, Nanfang Hospital, Southern
Medical University, Guangzhou North Avenue 1838#, Guangzhou 510515, China.

Keywords: Refeeding syndrome, Hypophosphatemia, Nutrition, Neurocritical illness

ABSTRACT
Background and aim: Neurocritically ill patients are more likely to be comatose and
suffer from dysphagia, conditions that inevitably require nutritional support. Inappropriate
nutritional support may lead to refeeding syndrome (RFS). This study aimed to explore the
incidence and outcome of RFS in neurocritically ill patients.
Methods: We conducted a retrospective study among neurocritically ill patients who

received total enteral nutrition for > 72 hours in a university-affiliated hospital. RFS was

defined as the occurrence of new-onset hypophosphatemia (< 0.65 mmol/L) within 72

hours of the commencement of nutritional support. The primary outcome was 6-month
mortality. The secondary outcomes included 30-day mortality, neurocritical care unit
(NCU) stay, and hospital length of stay.
Results: A total of 328 patients were enrolled, and 56 (17.1%) of them developed RFS
within 72 hours of nutrition support. Significantly, we found that patients with high
malnutrition universal screening tool (MUST) and sequential organ failure assessment
(SOFA) scores were more likely to develop RFS. The occurrence of RFS was associated
with a longer NCU stay, higher 30-day mortality and 6-month mortality, and poorer
6-month functional outcome. Moreover, RFS was identified as an independent risk factor
for 6-month mortality.
Conclusion: RFS is not rare in neurocritically ill patients and is more likely to occur in
patients with nutritional risk and more severe conditions. RFS is an independent risk factor
for 6-month mortality in neurocritically ill patients.
Introduction
Refeeding syndrome (RFS) refers to the biochemical and clinical symptoms and
metabolic abnormalities in malnourished patients undergoing refeeding, whether induced
by oral, enteral, or parenteral feeding [1]. The RFS syndrome is usually characterized by
low serum concentrations of predominately intracellular ions such as phosphate,
magnesium, and potassium, but abnormalities in the metabolism of glucose, thiamine,
and levels of sodium and water balance have been frequently noted [1]. These
biochemical abnormalities could cause consequential metabolic disturbances to the
cardiac, respiratory, hepatic, hematological, and neuromuscular systems and ultimately
lead to multiple organ dysfunction and death [2]. Although there is no strong evidence
connecting RFS and adverse outcomes, many studies have reported increased mortality
and disability rates after the occurrence of RFS [3, 4].
The incidence of RFS varies among reported studies, ranging from 0% to 80%, due to
the lack of a universally accepted definition and objective diagnostic criteria [4]. Most
studies used hypophosphatemia or a rapid decline of serum phosphorus from baseline as
part of the definition of RFS. In a randomized clinical trial undertaken in any patient
population with RFS conducted by Doig and colleagues [5], RFS was defined as
new-onset hypophosphatemia with a fall of phosphate levels > 0.16 mmol/L to below
0.65 mmol/L. By using this definition of RFS, a recent study found an incidence of 34%
among critically ill, invasive mechanically ventilated patients admitted for > 7 days to a
medical-surgical intensive care unit (ICU) [6]. The incidence of RFS also varies among
different study populations and nutritional approaches [4]. Although the National
Institute for Health and Care Excellence (NICE) guidelines have indicated risk factors for
RFS [7], two recent studies showed that only 30% of RFS patients could be identified by
the NICE guidelines because of its low sensitivity [8, 9]. Other factors, such as age, low
albumin, high nutritional intake, low insulin-like growth factor-1, and enteral feeding
should also be considered when developing nutritional support strategies for different
populations.
Since the 1980s, neurocritical care has grown into an organized subspecialty focusing
on the optimal management of acutely ill patients with life-threatening neurologic and
neurosurgical diseases or with life-threatening neurologic manifestations of systemic
diseases, with the establishment of neurocritical care units (NCUs), and professional
organizations [10]. Compared with those in general intensive care units (ICUs), patients
in NCUs were more likely to be transferred from an outside hospital, had a lower rate of
mechanical ventilation, a longer ICU length of stay, and a higher rate of tracheostomy
[11]. More important, more patients with neurological diseases tend to develop
malnutrition due to multiple causes, including but not limited to oropharyngeal dysphagia,
impaired consciousness, perception deficits, cognitive dysfunction, and increased
metabolic demand [12]. Therefore, neurocritically ill patients usually require more
nutrition support, predominantly enteral nutrition, and the latter is regarded as a risk
factor of refeeding hypophosphatemia [9]. However, little evidence is available on the
incidence and risk factors of RFS in neurocritically ill patients. In addition, the influence
of RFS on clinical outcomes in neurocritically ill patients remains to be elucidated.
In the present study, we aimed to investigate the incidence of RFS in neurocritically ill
patients at nutritional risk and receiving full enteral feeding. Moreover, we sought to find
out whether the occurrence of RFS was associated with higher mortality and morbidity in
these patients.

Materials and Methods

2.1. Study description
This is a single-center, observational, retrospective cohort study. The study proposal
was approved by the Nanfang Hospital’s Ethics Committee on clinical research. Informed
consent was waived by the review board because of its observational and retrospective
properties, and all data was fully de-identified. This manuscript adheres to the applicable
STROBE guidelines.
2.2 Study population
We screened all patients admitted to the NCU of Nanfang Hospital, a
university-affiliated academic hospital, between January 2013 and April 2019. The
criteria for NCU admission were Glasgow Coma Scale (GCS) < 12 and/or admission for
APACHE II score > 15. Otherwise, they were still included if meeting one of the criteria
as follows: severe cerebral infarction defined as infarction of more than two-thirds of
middle cerebral artery territory for supratentorial stroke; massive cerebellar infarction
defined as infarction involving at least territory of the superior cerebellar artery or
anterior inferior cerebellar artery or posterior inferior cerebellar artery with or without
impairment of consciousness or mass effect on computed tomography; locked-in
syndrome; top of the basilar syndrome; severe brain stem infarction; severe intracerebral
hemorrhage defined as hematoma volume of more than 20 ml for the supratentorial
hemorrhage; cerebellar hemorrhage of more than 3 cm in diameter, brain stem
hemorrhage of more than 5 ml; severe intracranial infection, status epilepticus, high
intracranial pressure more than 300 mmHg; neurologic disease of the spinal cord,
peripheral nerves and so on, resulting in respiratory failure requiring endotracheal
intubation and/or mechanical ventilation; and neurologic diseases with severe medical
comorbidity such as cardiac arrhythmia, pneumonia, and organ failure needing intensive
care. [13,14]. If patients were readmitted to the NCU during the same admission period,
only the first admission was evaluated. In our computerized system, data on energy
intake, calculated daily targets, laboratory results (including potassium, phosphate,
magnesium, and glucose), electrolytes, and glucose supplementation were accurately
recorded for all admitted patients during the NCU admission period.
Patients were included in this study if they (1) were on fully enteral feeding for > 72
hours during NCU study; (2) had serum hypophosphatemia records before enteral feeding
(baseline) and at 72 ± 12 hours after feeding. Patients were excluded if they (1) had
incomplete data on nutritional provision; (2) were aged > 85 or < 18 years; (3) had serum
phosphate < 0.65 mmol/L at NCU admission; (4) were lost to follow-up; (5) had
end-stage malignant diseases; (6) had complications from diabetic ketoacidosis; or (7)
had recent parathyroidectomy or were receiving renal replacement therapy, using
phosphate binders, or undergoing therapeutic hypothermia.
2.3 RFS definition and data collection
RFS was defined as the occurrence of new-onset hypophosphatemia within 72 hours of
the start of nutritional support. Hypophosphatemia was defined, based on recent literature
[5, 6], as a drop of serum phosphate > 0.16 mmol/L from any previous measurement to
below 0.65 mmol/L. Severe hypophosphatemia was defined as serum phosphate ≤ 0.32
mmol/L. Baseline serum phosphate ([P0]) referred to phosphorus measured at the nearest
point in time before receiving nutritional support. Minimum serum phosphate ([P]min) and
maximum serum phosphate ([P]max) from baseline to 72 hours of nutritional support were
also recorded. We calculated the fluctuation of serum phosphate as ∆[P] = [P]max − [P]min.
The electronic medical records of all patients were carefully reviewed, and
demographic information, final diagnoses, and pre-existing comorbidities were recorded.
The duration from the onset of illness to our NCU admission, our NCU stay, and hospital
stay were also collected. The worst laboratory data within 24 hours of NCU admission,
including serum potassium, sodium, and magnesium, were obtained. In our NCU, each
patient was evaluated with GCS at NCU admission and with Acute Physiology and
Chronic Health Evaluation II (APACHE II) [5] and sequential organ failure assessment
(SOFA) [15] within 24 hours of NCU admission.
2.4 Nutrition management
Each patient routinely received nutritional risk screening (NRS) 2002 upon NCU
admission [16], and individual nutritional strategies for each patient were developed
based on the temporal clinical guidelines [17, 18]. According to the NICE guidelines [19],
patients at risk of developing RFS were stratified and had their daily calories intake
limited. In general, we provided enteral nutritional support to patients within 24 hours of
NCU admission and minimized interruption of nutritional support to ensure that each
patient achieved nutritional goals as soon as possible. The total calories per day for the
first three days of each patient were calculated here. In this study, we also respectively
obtained the Nutrition Risk in Critically ill patients (NUTRIC) score [20] and
malnutrition universal screening tool (MUST) score [21] for nutritional risk assessment at
NCU admission.
2.4 Outcome
The primary outcome was 6-month mortality. The secondary outcomes were 30-day
mortality, 6-month poor outcome defined as modified Rankin Scale (mRS) of > 3, the
length of NCU, and the length of hospital stay. Outcome data on mortality and functional
recovery was obtained by two trained neurologists who were blinded to other study data.
2.5 Data analyses and statistical considerations

Descriptive data for patient characteristics was calculated for all variables. Categorical
variables were presented as number (%) and were compared using the two-sided
Chi-square test or Fisher’s exact test. Continuous data was reported as mean ± standard
deviation (SD) or as median (interquartile range [IQR]), depending on data distribution,
and were analyzed using independent t-test or Mann-Whitney U test. When necessary,
continuous variables were dichotomized or categorized. The whole study sample was
then divided into the RFS and non-RFS groups. Univariable analysis was performed first,
and candidate variables that had a p-value less than 0.05 were drawn into corresponding
multivariable logistic regression models. Candidate variables included demographic data
(age, sex), comorbidity (diabetes, hypertension, heart disease), indicators of critical
illness (APACHE II, GCS, SOFA, mechanical ventilation at admission), nutritional risk
(MUST, NRS 2002, NUTRIC), and energy management (the calorie of the first three
days). The 95% confidence intervals (CIs) reported for the logistic regression odds ratios
(ORs) were calculated by the Wald estimation.
To evaluate the influence of RFS, including [P0], ∆[P] on 30-day mortality or 6-month
mortality, logistic regression analysis was used. Data analysis was performed using SPSS
Statistics for Windows (version 17.0). For all analyses, p < 0.05 was considered
statistically significant.

3. Result
3.1 Patient characteristics
Of the 1770 patients screened, 328 were regarded as eligible and finally included
(Figure 1). This cohort consisted of patients with ischemic stroke (n = 124), intracerebral
hemorrhage (n = 68), intracranial infection (n = 54), and other neurologic diseases (n =
82). The average age of the enrolled patients was 56.5 ± 16.5 years, and 229 (69.8%) of
them were male. The mean APACHE II score was 15 ± 6, and the median (IQR) length
of NCU stay was 9 (5 -14) days. Of the enrolled patients, 56 (17.1%) developed RFS
within 72 hours of nutrition support (Figure 1), and nine (2.7%) had severe
 hypophosphatemia.

Figure 1. Patient inclusion flowchart.

3.2 Risk factors for RFS in neurocritically ill patients

The median P0 was 1.0 mmol/L (0.8−1.2 mmol/L) in the RFS group and 1.1 mmol/L
(0.9–1.2 mmol/L) in the non-RFS group. Other baseline demographics and clinical
characteristics of these two groups are summarized in Table 1. There were no significant
differences in baseline potassium, sodium, magnesium, diabetes, hypertension, heart
disease, and day 1 and day 3 caloric intakes (kcal) between the RFS and non-RFS groups.
However, patients with RFS had lower GCS and higher APACHE II, SOFA, MUST, and
NUTRIC scores than those without RFS. In addition, patients in the RFS group received
fewer calories on day 2 than those in the RFS group.

Table 1. Patient characteristics based on refeeding syndrome

Variables RFS (n = 56) non-RFS (n = 272) P

Female, n (%) 14 (25%) 85 (31%) 0.354
Age, years, median [IQR] 62 [48-76] 58 [45-68] 0.082
Duration from the onset of diseases to our
2 [0-11] 4 [1-12] 0.320
NCU, days, median [IQR]
Comorbidities
History of alcoholism, n (%) 3 (5%) 29 (11%) 0.223
Diabetes mellitus, n (%) 10 (18%) 53 (20%) 0.778
Hypertension, n (%) 32 (57.1%) 131 (48.2%) 0.221
Heart disease, n (%) 10 (17.9%) 31 (11.4%) 0.183
Mechanical ventilation at admission, n (%) 5 (8.9%) 26 (9.6%) 0.883
Baseline scores
APACHE II, median [IQR] 17 [14-21] 15 [10-19] 0.003
GCS, median [IQR] 7 [5-11] 9 [6-12] 0.030
SOFA, median [IQR] 6 [4-8] 4 [3-6] 0.014
NUTRIC, median [IQR] 4 [3-5] 3 [2-4] 0.004
NRS 2002, median [IQR] 4 [3-5] 4 [3-4] 0.140
MUST, median [IQR] 2 [2-2] 2 [2-2] 0.017
Baseline electrolyte in serum
P0, mmol/L, median [IQR] 1.0 [0.8-1.2] 1.1 [0.9-1.2] 0.939
Potassium, mmol/L, mean ± SD 4.0 ± 0.6 3.9 ± 0.5 0.358
Sodium, mmol/L, median [IQR] 139 [135-144] 140 [137-143] 0.348
Magnesium, mmol/L, median [IQR] 0.8 [0.8-0.9] 0.9 [0.8-0.9] 0.079
Caloric intakes within the first 72 hours
Day1 (Kcal), median [IQR] 550 [450-550] 550 [450-550] 0.440
Day2 (Kcal), median [IQR] 900 [900-1100] 1000 [900-1100] 0.003
Day3 (Kcal), median [IQR] 1350 [1100-1650] 1350 [1100-1650] 0.815
Outcomes
LOS, days, median [IQR] 22 [11-33] 19 [12-32] 0.862
Length of NCU stay, median [IQR] 10 [6-19] 8 [5-14] 0.046
6-month mortality 25 (44.6%) 68 (25.0%) 0.003
30-day mortality, n (%) 22 (39.3%) 60 (22.1%) 0.007
6-month good outcome (mRS ≤ 3), n (%) 15 (26.8%) 127 (46.7%) 0.006
RFS, refeeding syndrome; APACHE II, Acute Physiology and Chronic Health
Evaluation II; NUTRIC, Nutrition Risk in Critically ill patients; GCS, Glasgow Coma
Scale; SOFA, Sequential Organ Failure Assessment; IQR, interquartile range. MUST,
malnutrition universal screening tool; NRS 2002, nutritional risk screening 2002; P0,
baseline serum phosphorous; LOS, length of hospital stay. NCU, neurocritical care unit;
mRS, modified Rankin Scale

To explore the risk factors of RFS, several multivariable models were established by
including relevant parameters and in combined consideration of collinearity. In Model A,
which included day 2 caloric intake and MUST and SOFA scores, MUST (OR 1.783,
95% CI 1.032~3.080) and SOFA (OR 1.112, 95% CI 1.009~1.225) were found
significantly associated with the development of RFS (Table 2). In Model B, which
included day 2 caloric intake and MUST and APACHE II scores, MUST (OR 1.762, 95%
CI 1.012~3.069) and APACHE II (OR 1.068, 95% CI 1.018~1.121) were found to be
independent risk factors for RFS (Supplementary Table S1).

Table 2. Logistic regression analysis to identify predictors of RFS

Univariable analysis* Multivariable analysis
Variables
OR 95% CI P OR 95% CI P
Day 2 (Kcal) 0.999 0.998-1.000 0.040 - - -
MUST 1.775 1.033-3.049 0.038 1.783 1.032-3.080 0.038
SOFA 1.112 1.009-1.225 0.032 1.112 1.009-1.225 0.032
MUST, malnutrition universal screening tool; SOFA, sequential organ failure
assessment; CI, confidence interval; OR, Odds ratio. *only variables included for
multivariable analysis were shown. APACHE II and GCS were not included because of
potential collinearity with SOFA. NUTRIC was not included because of potential
collinearity with MUST and SOFA.

3.2 Primary outcome

During follow-up, 82 (25%) of all the enrolled patients died within 30 days after
admission, and 93 died (28.4%) within six months. A total of 142 (43.3%) patients
achieved a good outcome at six months. Compared with patients without RFS, patients
with RFS were associated with longer NCU stay, increased 30-day mortality, 6-month
mortality, and 6-month poor outcome (Table 1). Significantly, the occurrence of RFS was
associated with an increase in odds of 6-month mortality (OR = 2.419; 95% CI,
1.336~4.382; p = 0.004) (Table 3). Other factors showed association with 6-month
mortality included age, heart disease, APACHE II, GCS, SOFA, NUTRIC, NRS 2002,
MUST and ∆P (Supplementary Table S2). In the multivariable model, RFS was identified
as an independent risk factor of 6-month mortality, along with age and SOFA (Table 3).
 Table 3. Logistic regression analysis to identify predictors of 6-month mortality
Univariable analysis* Multivariable analysis
Variables
OR 95%CI P OR 95%CI P
Age 1.040 1.023-1.058 0.000 1.040 1.022-1.059 0.000
SOFA 1.213 1.109-1.326 0.000 1.217 1.107-1.338 0.000
RFS 2.419 1.336-4.382 0.004 1.940 1.020-3.688 0.043
∆Phosphorus 2.049 1.062-3.952 0.032 - - -
MUST 1.712 1.038-2.822 0.035 - - -
Heart disease 2.792 1.432-5.443 0.003 - - -
SOFA, sequential organ failure assessment; RFS, refeeding syndrome; MUST,
malnutrition universal screening tool; CI, confidence interval; OR, odds ratio. * only
variables included for multivariable analysis were shown. APACHE II and GCS were not
included because of potential collinearity with SOFA. NUTRIC and NRS 2002 were not
included because of potential collinearity with MUST.

In terms of 30-day mortality, ∆P and RFS were associated with increased risk of
30-day mortality with ORs (95%CI) of 2.033 (1.042~3.967) and 2.286 (1.245~4.200),
respectively (Table 4 & Supplementary Table S3). Nevertheless, these indicators were
not independently related to 30-day mortality in multivariable models, while age, GCS,
and NRS 2002 were independent risk factors of 30-day mortality (Table 4). Similarly,
RFS was not independently associated with 6-month poor outcome after adjustment for
confounders (Supplementary Table S4 & S5).

Table 4. Logistic regression analysis to identify the predictors of 30-day mortality

Univariable analysis* Multivariable analysis
Variables
OR 95%CI P OR 95%CI P
Age 1.033 1.016-1.051 0.000 1.032 1.013-1.051 0.001
GCS 0.867 0.805-0.934 0.000 0.859 0.792-0.931 0.000
NRS 2002 1.728 1.300-2.296 0.000 1.371 1.003-1.874 0.048
∆Phosphorus 2.033 1.042-3.967 0.037 - - -
Heart disease 2.727 1.386-5.364 0.004 - - -
RFS 2.286 1.245-4.200 0.008 - - -
GCS, Glasgow Coma Scale; NRS 2002, nutritional risk screening 2002; RFS, refeeding
syndrome; CI, confidence interval; OR, odds ratio. * only variables included for
multivariable analysis were shown. APACHE II and SOFA were not included because of
potential collinearity with GCS. NUTRIC and NRS 2002 were not included because of
potential collinearity with MUST.

4. Discussion
Our results demonstrated that RFS is not rare in neurocritically ill patients, with an
incidence of 17.1% within 72 hours of nutrition support. High MUST and SOFA scores
were independent risk factors for RFS, and the occurrence of RFS was associated with a
longer NCU stay and mortality at 30 days and six months, revealing that RFS should be
regarded as critical because it has not been frequently studied in the NCU.
The prevalence of RFS in this study was lower than that reported by Olthof et al. [6],
who showed an incidence of 36.8%, using similar definitions in a mixed medical-surgical
ICU population. The probable reason for the divergent incidence may be that the patients
in Olthof’s study were older and had higher APACHE II scores, and all of their patients
underwent mechanical ventilation. Furthermore, the caloric intake was different between
Olthof’s and our study because we used restricted caloric intake according to NICE’s risk
stratification of RFS, whereas only 30% of patients received hypocaloric intake in
Olthof’s study. Flesher et al. [22] found a higher incidence (80%), using a different
definition of RFS, which was as follows: depletions in phosphate, magnesium, or
potassium after initiation of enteral feeding. In another study, Hoffman et al. [23] found
the rate of hypophosphatemia to be 45% in an ICU. However, this rate was for all causes
of hypophosphatemia, not just for refeeding hypophosphatemia. Thus, the highly
heterogeneous definitions of RFS contributed to different incidence rates of RFS.
Although the NICE criteria are widely used to identify patients at high risk of
refeeding problems, only about 30% of patients could be screened [8, 9]. Therefore, other
risk factors may contribute to RFS while not being included in the NICE criteria. Here,
we observed that high SOFA and MUST scores were associated with increased odds of
RFS, which suggests that RFS is not only determined by malnutrition status as reflected
by the MUST score, but also in connection with disease severity as reflected by the
SOFA score (or APACHE II score, see Supplementary Table S1). These results are
concordant with a recent study conducted by Ralib et al. [24], who showed that risk
factors for RFS include high SOFA and low baseline serum magnesium. The reason
SOFA was attached to RFS may due to the increase in nutritional requirements,
impairment of food intake, and increased stress-metabolism resulting from the disease
[16]. Furthermore, a low baseline level of magnesium [25] and older age [26] were
reported to be risk factors for RFS; however, we did not find such association in the
current study.
In terms of adverse outcome, we identified RFS as an independent risk factor for
6-month mortality, and RFS was related to increased odds of 30-day mortality and
6-month poor outcome. Several studies have drawn similar conclusions about the
connection between hypophosphatemia and increased mortality [27-29]. A retrospective
study that enrolled 117 patients showed that RFS, which was defined as a serum P level
of ≤ 2.4 mg/L (0.77 mmol/L), was associated with increased mortality and ICU length of
stay [29]. It is suggested that hypophosphatemia can result in cardiac arrhythmia,
respiratory failure, rhabdomyolysis, and confusion [30-32]. Firstly, hypophosphatemia
may lead to respiratory muscle dysfunction, potentially resulting in respiratory failure,
and the latter could cause longer durations of mechanical ventilation and length of
hospital study. Second, the metabolic rate of platelets, red blood cells, and white blood
cells are regulated by serum phosphate. White blood cells with reduced intracellular
levels of adenosine triphosphate (ATP) have substantially impaired chemotactic,
phagocytic, and bactericidal abilities. Therefore, metabolic rate dysfunction is associated
with infection and increased mortality. Similarly, red blood cell dysfunction shifts the
oxygen dissociation curve to the left, decreasing oxygen delivery to peripheral tissue
[33,34], which exacerbates respiratory failure. In a recent study of critically ill patients,
Olthof et al. [6] did not find significant difference in clinical outcome between those with
and without RFS, but in the subgroup analysis they observed that patients who developed
RFS and continued to receive high caloric intake were associated with higher mortality.
Standard treatment for RFS comprises close monitoring and correction of fluid
imbalances, phosphate, and other electrolytes and thiamine supplementation. The NICE
guidelines recommend commencing nutritional support for patients at risk of developing
RFS at a maximum of 50% of requirements for the first three days, increasing levels
slowly to meet the full target by days 4 -7 [6]. Recently, an elegant randomized
controlled trial conducted by Doig and colleagues showed that the full caloric strategy
was associated with higher mortality at 60 and 90 days in patients who developed RFS,
while caloric restriction significantly reduced the incidence of major infections, in
particular respiratory infections [5]. The European Society for Clinical Nutrition and
Metabolism (ESPEN) guideline on clinical nutrition in the intensive care unit has now
recommened considering caloric restriction during the first 72 h to facilitate control of
electrolyte disturbances if RFS is anticipated or detected [35].
In our NCU, standard care for RFS consisted of correcting fluid and electrolyte
imbalances as well as supplementating the thiamin level. Restricting caloric intake during
RFS management was not implemented, because the recommendation from ESPEN
guideline has only recently become available [35], and that should be a limitation to this
study. Nevertheless, energy intake in individual patients may vary markedly due to
feeding practicalities such as enteral feeding intolerance and the use of non-nutritional
calories.
There were several limitations to this study. First, it was a retrospective study;
information was retrieved from patient records. Thus, a large number of potentially
eligible participants could not be included due to the missing serum phosphate data either
at NCU admission or at 72 hours after enteral nutrition support, potentially leading to
selection bias and residual confounding. Second, due to the relatively small number in the
RFS group, we did not divide it into several subgroups to analyze the difference among
diverse diseases, which requires further research. Third, we were not able to obtain the
detailed nutrition support information of all included subjects before admission to our
NCU. However, we used the NRS 2002 score and the MUST score to assess nutritional
risk at admission.

5. Conclusion
RFS is not rare in neurocritically ill patients, and high SOFA and MUST scores are
associated with increased odds of RFS. Moreover, the development of RFS within 72
hours after the start of nutritional support is associated with increased 6-month mortality.
To our knowledge, this is the first study to evaluate the incidence and outcome of RFS in
neurocritically ill patients.

Conflicts of interest
The authors have disclosed that they do not have any conflicts of interest.

Statement of authorship
K.H. and S.P. had full access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Study concept and design: K.H., S.P.
Acquisition of data: R.X., H.H., S.W., D.W.
Interpretation of data and statistical analysis: Y.W., Z.L.
Drafting the manuscript: R.X., H.H.
Critical revision of the manuscript for important intellectual content: K.H., S.P., Y.W.,
N.Z.
Administrative, technical, or material support: Y.W., Z.J.
Study supervision: K.H, S.P.
Final approval of the version submitted: X.R., H.H., Y.W., S.W., D.W., Z.J., Z.L., S.P.,
K.H.

Acknowledgment
None.

Funding
This study was supported by the National Key R&D Program of China (No.
2017YFC1307500), National Natural Science Foundation of China (No. 81701294 &
81871030), Natural Science Foundation of Guangdong Province (2019A1515011446),
and Guangzhou Science and Technology Planning Project (No. 201804010055).
References
[1]. van Zanten, A.R.H., Nutritional support and refeeding syndrome in critical illness.
Lancet Respir Med, 2015. 3(12): 904-5.
[2]. Stanga, Z., et al., Nutrition in clinical practice-the refeeding syndrome: illustrative
cases and guidelines for prevention and treatment. Eur J Clin Nutr, 2008. 62(6): 687-94.
[3]. Kraaijenbrink, B.V., et al., Incidence of refeeding syndrome in internal medicine
patients. Neth J Med, 2016. 74(3): 116-21.
[4]. Friedli, N., et al., Revisiting the refeeding syndrome: Results of a systematic review.
Nutrition, 2017. 35: 151-60.
[5]. Doig, G.S., et al., Restricted versus continued standard caloric intake during the
management of refeeding syndrome in critically ill adults: a randomised, parallel-group,
multicentre, single-blind controlled trial. Lancet Respir Med, 2015. 3(12): p. 943-52.
[6]. Olthof, L.E., et al., Impact of caloric intake in critically ill patients with, and
without, refeeding syndrome: A retrospective study. Clin Nutr, 2018. 37(5): 1609-17.
[7]. UK, N.C.C.F., Nutrition Support for Adults: Oral Nutrition Support, Enteral Tube
Feeding and Parenteral Nutrition. National Institute for Health and Clinical Excellence:
Guidance. 2006, London: National Collaborating Centre for Acute Care (UK).
[8]. Goyale, A., et al., Predicting refeeding hypophosphataemia: insulin growth factor 1
(IGF-1) as a diagnostic biochemical marker for clinical practice. Ann Clin Biochem,
2015. 52(Pt 1): 82-7.
[9]. Zeki, S., et al., Refeeding hypophosphataemia is more common in enteral than
parenteral feeding in adult in patients. Clin Nutr, 2011. 30(3): 365-8.
[10]. Moheet, A.M., et al., Standards for Neurologic Critical Care Units: A Statement for
Healthcare Professionals from The Neurocritical Care Society. Neurocrit Care, 2018.
29(2): 145-60.
[11]. Kurtz, P., et al., How Does Care Differ for Neurological Patients Admitted to a
Neurocritical Care Unit Versus a General ICU? Neurocrit Care, 2011. 15(3): 477-80.
[12]. Burgos, R., et al., ESPEN guideline clinical nutrition in neurology. Clin Nutr, 2018.
37(1): 354-396.
[13]. Su, Y., et al., Predicting hospital mortality using APACHE II scores in
neurocritically ill patients: a prospective study. J Neurol, 2009. 256(9): 1427-33.
[14]. Bai, M., et al., Prognostic value of C-reactive protein/albumin ratio in
neurocritically ill patients. Minerva Anestesiol, 2019. 85(12): 1299-307.
[15] Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) Score to
Describe Organ Dysfunction/Failure. On Behalf of the Working Group on Sepsis-Related
Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996,
22 (7): 707-10.
[16]. Kondrup, J., et al., Nutritional risk screening (NRS 2002): a new method based on
an analysis of controlled clinical trials. Clin Nutr, 2003. 22(3): 321-36.
[17]. McClave, S.A., et al., Guidelines for the Provision and Assessment of Nutrition
Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine
(SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J
Parenter Enteral Nutr, 2009. 33(3): 277-316.
[18]. McClave, S.A., et al., Guidelines for the Provision and Assessment of Nutrition
Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine
(SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J
Parenter Enteral Nutr, 2016. 40(2): 159-211.
[19]. De Silva, A., T. Smith and M. Stroud, Nice on refeeding syndrome - Attitudes to
NICE guidance on refeeding syndrome. BMJ, 2008. 337: a680.
[20]. Heyland, D.K., et al., Identifying critically ill patients who benefit the most from
nutrition therapy: the development and initial validation of a novel risk assessment tool.
Crit Care, 2011. 15(6): R268.
[21]. Collins, P.F., et al., The influence of deprivation on malnutrition risk in outpatients
with chronic obstructive pulmonary disease (COPD). Clin Nutr, 2018. 37(1): 144-8.
[22]. Flesher, M.E., et al., Assessing the metabolic and clinical consequences of early
enteral feeding in the malnourished patient. JPEN J Parenter Enteral Nutr, 2005. 29(2):
108-17.
[23]. Hoffmann, M., et al., Hypophosphataemia at a large academic hospital in South
Africa. J Clin Pathol, 2008. 61(10): 1104-7.
[24]. Ralib, A.M. and M.B.M. Nor, Refeeding hypophosphataemia after enteral nutrition
in a Malaysian intensive care unit: risk factors and outcome. Asia Pac J Clin Nutr, 2018.
27(2): 329-335.
[25]. Rio, A., et al., Occurrence of refeeding syndrome in adults started on artificial
nutrition support: prospective cohort study. BMJ Open, 2013. 3(1): e002173.
[26]. Gonzalez Avila, G., A. Fajardo Rodriguez and E. Gonzalez Figueroa, [The
incidence of the refeeding syndrome in cancer patients who receive artificial nutritional
treatment]. Nutricion hospitalaria, 1996. 11(2): p. 98-101.
[27]. Vignaud, M., et al., Refeeding syndrome influences outcome of anorexia nervosa
patients in intensive care unit: an observational study. Crit Care, 2010. 14: R1725.
[28]. Kagansky, N., et al., Hypophosphataemia in old patients is associated with the
refeeding syndrome and reduced survival. J Intern Med. 2005. 257(5): 461-8.
[29]. Coskun, R., et al., Refeeding hypophosphatemia: a potentially fatal danger in the
intensive care unit. Turk J Med Sci. 2014. 44(3): 369-74.
[30]. Marinella, M.A., Refeeding syndrome and hypophosphatemia. J Intensive Care Med,
2005. 20(3): 155-9.
[31]. Whyte, E., P. Jefferson and D.R. Ball, Anorexia nervosa and the refeeding
syndrome. Anaesthesia, 2003. 58(10): 1025-6.
[32]. Crook, M.A., V. Hally and J.V. Panteli, The importance of the refeeding syndrome.
Nutrition, 2001. 17(7-8): 632-7.
[33]. Lichtman, M.A., et al., Reduced red cell glycolysis, 2, 3-diphosphoglycerate and
adenosine triphosphate concentration, and increased hemoglobin-oxygen affinity caused
by hypophosphatemia. Ann Intern Med, 1971. 74(4): 562-8.
[34]. Larsen, V.H., et al., Erythrocyte 2,3-diphosphoglycerate depletion associated with
hypophosphatemia detected by routine arterial blood gas analysis. Scand J Clin Lab
Invest Suppl, 1996. 224: 83-7.
[35]. Singer, P., et al., ESPEN guideline on clinical nutrition in the intensive care unit.
Clin Nutr, 2019. 38(1): 48-79.