Non-inferiority Comparative Clinical Trial Between Early Oral Refeeding Versus Usual Oral Refeeding in Mild Acute Pancreatitis Patients
Phase: NA
Conditions: Pancreatitis
Sponsor: Hospital Regional de Alta Especialidad del Bajio

NON-INFERIORITY COMPARATIVE CLINICAL TRIAL BETWEEN EARLY ORAL 
REFEEDING VERSUS USUAL ORAL REFEEDING IN MILD ACUTE 
PANCREATITIS PATIENTS 
 
 
Edgard Efren Lozada-Hernández,a*  
Omar Barrón Gonzálezb 
Santa Vázquez Romeroc  
Martin Cano Rosasd  
Evelia Apolinar Jimeneze 
Author 
a Departament of surgery and clinical research, Hospital Regional de Alta Especialidad del 
Bajío, León Guanajuato, México. 
Co-authors: 
b Departament of Surgery, Unidad Médica de Alta Especialidad Bajío, Instituto Mexicano 
del Seguro Social. León, Guanajuato, México.  
c Departament of surgery, Unidad Médica de Alta Especialidad Bajío, Instituto Mexicano 
del Seguro Social. León, Guanajuato, México 
d Departament of surgery, Unidad Médica de Alta Especialidad Bajío, Instituto Mexicano 
del Seguro Social. León, Guanajuato, México 
e Departament of clinical nutrition, Hospital Regional de Alta Especialidad del Bajío, León 
Guanajuato, México.   
 
Corresponding author 
*Edgard Efrén Lozada Hernández 
Circuito Quinta los Naranjos # 145 B. Colonia Quinta los Naranjos 
Telephone number: +52 1 477 274 5801 
E-mail: edgardlozada@hotmail.com  
 
 
 

 
Abstract 
Background The aim of the study is to compare the onset of oral feeding in the first 24 hours 
after hospital admission and determine if this influences the recurrence of pain or alters the 
blood levels of pancreatic enzymes, compared to usual oral refeeding in patients with mild 
acute pancreatitis 
Methods This Non-Inferiority Randomized controlled trial was carried out between September 
2018 and June 2019, prior authorization from the ethics committee in health research. Patients 
with diagnosis of mild acute biliary pancreatitis, were divided into: Group A (early oral 
refeeding) and Group B (usual oral refeeding). Outcome measures were lipase pancreatic, 
systemic inflammatory response (concentrations of leukocytes) were used as marker for it, 
feasibility evaluated by abdominal pain recurrence, presence and recurrence of 
gastrointestinal symptoms and length of hospital stay. 
Results Two patients of the EOR group had pain relapse (3.2%) and four of the UOR group 
(6.77%) after oral refeeding (p= 0.379). The presence of nausea or vomiting after onset of 
oral refeeding does not show differences (p= 0.293). The start time of the oral refeeding 
was approximately 48 h longer in the UOR group. Hospital length was 5 days in the group 
EOR and 8 days for the UOR group (p = 0.042); and this difference was also manifested in 
the hospital cost being higher in the group UOR p = 0.0235 
 
Conclusion The early oral refeeding is safe in mild acute pancreatitis patients, without 
adverse gastrointestinal events, and reduce the hospital stay and cost compared with usual 
oral refeeding. 
Trial registration:  Local Committee 1001 registration number 17 CI 11020146 
CPFEPRIS. Trial registration number R-2018-1001-074 August 28, 2018. 
 
 
 
 
 
 
 
 
 
 
 

 
Keywords 
Mild acute pancreatitis 
Oral refeeding 
Non inferiority clinical trial 
Nil per oral 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
BACKGROUND 
Acute pancreatitis (AP) is an inflammatory pancreatic process, presents different severity 
degrees [1]. Over the last two decades, there has been a paradigm shift in the management, 
from surgical to “step up” approach using percutaneous or endoscopic catheter drainage 
followed by minimally invasive necrosectomy [2]. As no curative therapy is currently 
available for AP, early treatment consists of supportive care which includes adequate fluid 
resuscitation, pain management and enteral nutrition [3]. Pancreatic rest by Nil Per Oral 
(NPO) strategy was considered necessary in AP till abdominal pain get resolved and the 
levels of pancreatic and inflammatory markers decrease [4]. This trend has changed, now it 
is clear that the early oral refeeding for PA mild does not only provide adequate caloric 
intake, it may also improve clinical outcomes. It has been hypothesized that the combination 
of disturbed intestinal motility, microbial overgrowth and increased permeability of the gut 
can lead to bacterial translocation, thus causing infection of pancreatic necrosis [5,6]. 
The oral refeeding (OR) may reduce translocation by stimulating intestinal motility, reducing 
bacterial overgrowth and thereby maintaining mucosal gut integrity [7,8]. Also decrease 
infection complications, organ failure and mortality as compared with routine total parenteral 
nutrition [9,10]. In patients with (predicted) mild pancreatitis, numerous studies concluded 
that a normal oral diet can be resumed once the pain is decreasing [11-13], However, it 
remains unclear what the optimal time to do it is. There is still no consensus about the 
definition of “early” refeeding.  
The aim of the present study is to compare the onset of oral feeding in the first 24 hours 
after hospital admission and determine if this influences the recurrence of pain or alters the 
blood levels of pancreatic enzymes, compared to usual oral refeeding in patients with mild 
acute pancreatitis.  
 
METHODS 
 
Patients 
This Randomized controlled trial was carried out between September 2018 and June 2019, 
prior authorization from the ethics committee in health research. All patients admitted to the 
surgery services with diagnosis of acute biliary pancreatitis, whit mild episode criteria and 
symptom onset time less than 24 h, were screened for inclusion in the study.  Patients with 
pancreatitis from another cause other than biliary, pregnant, history of chronic pancreatitis, 
under 18 or over 75 years, and with moderately severe or severe acute biliary pancreatitis 
were excluded. Written informed consent was taken from all patients.  

A total number of 124 patients were randomized in this study. The sample size was calculated 
according to the formula published by Bouemn et all 2015 [14], in which a percentage of 
success was estimated with the standard treatment of 90% compared to the experimental 
management of 85%, with a margin of no less than 10%, with an alpha for a tail of 0.05%, 
and a beta of 20 %, with a percentage of estimated losses of approximately 10%, a total of 
62 patients per group was obtained.  
 
Definitions 
The diagnosis of AP was established when the patient presents two or more of the following 
three findings: typical abdominal pain, elevation of serum pancreatic enzymes (amylase 
and/or lipase) at more than three times the upper limit of the normal value, and imaging study 
(ultrasonography or computed tomography) suggestive of AP [15]. 
Severity Assessment 
Severity assessment of AP was done based on the revised Atlanta classification into mild, 
moderately severe and severe. Absence of organ failure or local or systemic complications 
was labelled as mild AP; of was defined using the modified Marshall scoring system [16]; 
and only the patients whose complete these severity criteria were randomized for the study.  
 
Protocol 
Once the diagnosis of acute biliary pancreatitis was confirmed and the course was mild, 
corresponding informed consent signed. 
Patients were divided into: Group A (early oral refeeding) and Group B (usual oral refeeding) 
through a table of random numbers generated with the commercial program IBM SPSS 
statistics number 25 (The numbers generated by the program were from the experimental 
group) 
Due to the characteristics of the study, only a simple blinding was possible (the doctor who 
performed the statistical analysis) 
Both groups were given medical management in the same manner as marked in the IAP and 
APA guidelines [17]. 
Fluid therapy with crystalloid solution (Hartmann), initial bolus of 10 mL / kg and followed 
by infusion for 24 h of 1.5 mL / kg / h. 
Pain management with opioid weak tramadol 50mg every 6 hours and paracetamol 1 gram 
every 8 hours with continuous evaluation of the analogue numerical scale to determine the 
need for extra doses 
 
Oral refeeding 

Group A: Early oral refeeding (EOR) Once the patient had a score of 1-3 of the analogue 
numerical scale (ENA), he was interrogated about symptoms such as nausea or vomiting, if 
he did not have them, then receives diet indicated between 16 and 24 hours after admission. 
Group B: usual oral refeeding (UOR) Once the attending physician decided according to his 
clinical judgment to restart the oral feeding. 
 
Type of Diet: 
In both groups, their initial diet was the same so that this did not influence the results to be 
measured.  
The soft diet consisted of one of 900 Kcal per day, with 86.7% carbohydrates (190 g), 13.3% 
protein (30 g) and 0% lipids (0 g); during 24 h. 
When the diet was adequately tolerated and there was no evidence of clinical complications 
or deterioration, normal diet was indicated, and the follow-up continues. 
 
Endpoints 
Outcome measures were amylase and lipase pancreatic-specific, systemic inflammatory 
response (concentrations of leukocytes) were used as marker for it, feasibility evaluated by 
abdominal pain recurrence, presence and recurrence of gastrointestinal symptoms and length 
of hospital stay. 
 
Data Collection: 
Laboratorial data, such as leukocytes, amylase and lipase were collected after inclusion in 
the study and after 24 and 48 h of oral refeeding. Clinical data records include age, gender, 
time from onset of pain baseline, Marshall score at admission and after start the oral feeding, 
gastrointestinal symptoms, abdominal pain, days until solid food intake, pain relapse, 
complications, length of hospital stay and readmissions. 
 
Statistical analysis 
Date are presented as frequency and percentage, comparisons between groups were using the 
χ2 test for binary data or Fisher´s exact test. Continuous variables are presented as median 
and range interquartile range and were compared using the Mann-Whitney U-test or t student 
test if they meet normal criteria. p-Values of less than 0.05 were considered significant. 
Statistical analyses were performed with SPSS version 25.0.0. Analysis by intention to treat 
was used. 
 
RESULTS 

A total of 120 patients were included in this study (61 in the EOR group and 59 in the group 
UOR). One patient from the EOR group was excluded because due to persistence of pain and 
for this reason he could not receive the oral refeeding. Three patients of the UOR group were 
excluded because: one patient had no pain improvement; tomography was performed and 
peripancreatic collections were demonstrated; two patients were operated without starting 
the oral refeeding.  These four patients not included in the study represent 3.2% of losses.  
The demographic data and clinical parameters of patients at admission are presented in the 
table 1. There was not statistically significance difference in both groups. 
 
The comparison of outcome variables between two groups as present in the table 2. Two 
patients of the EOR group had pain relapse (3.2%) and four of the UOR group (6.77%) after 
oral refeeding (p= 0.379). Another characteristic that determines tolerance to the OR is the 
presence of gastrointestinal symptoms, so the presence of nausea or vomiting after onset of 
oral refeeding does not show differences (p= 0.293). 
 
The lipase serum level could demonstrate recurrence, in the EOR group did not increase after 
the onset of the OR compared to the levels of admission. In the UOR group, decrease lipase 
serum level was observed comparing the baseline levels against the after start of OR levels, 
but it is expected, in fact was an inclusion criterion for this group. 
 
The systemic inflammatory response was evaluated with leukocyte levels, the behavior was 
very similar to that described in lipase levels, in the EOR group did not increase after the 
onset of the OR compared to the levels of admission 
 
 
The length of hospital and follow up as present in the table 3. The start time of the oral 
refeeding was approximately 48 h longer in the UOR group. Hospital length was 5 days in 
the group EOR and 8 days for the UOR group (p = 0.042); and this difference was also 
manifested in the hospital cost being higher in the group UOR p = 0.0235 
 
DISCUSSION 
For decades, pancreatic rest by Nil Per Oral (NPO) strategy was considered necessary in AP 
till abdominal pain get resolved and the levels of pancreatic and inflammatory markers 
normalize. This trend has changed now, early enteral feeding is accepted in the treatment of 
AP, but still have not consensus about of definition of early oral refeeding.  

The concept of the early oral refeeding includes the time between admission and the start the 
diet, and the presence of adverse event, that includes abdominal pain relapse and 
gastrointestinal symptoms (nausea and vomiting). 
In this study we found that the EOR is safe within the first 24 h after hospital admission, that 
there is no difference in the presence of abdominal pain relapse, nausea or vomiting compared 
with standard oral refeeding in mild acute pancreatitis. 
An unclear concept is the criteria for EOR, Eckerwall GE 2007 [11] report as criteria of 
starting OR “immediately allowed to drink” and the diet start time for his patients was one 
day. Teich N 2010 [13] it does not have a criterion; it was according to the randomization 
and the start time for his patients was two days. Li J 2013 [1] report as criteria of starting OR 
“feeling of hunger” and the start time for his patients was five days. Larino-Noia 2014 [18] 
report as criteria of starting OR “normal bowel sounds” and the diet start time for his patients 
was two days. Our criteria were the objective measurement of symptoms, the pain with a 
score of 3-10 on visual analogue scale, and the absence of symptoms like nausea or vomiting, 
these criteria allowed the OR to begin in the first 24 h, with a 95% success rate. 
Once start time of diet is defined, the next point to clarify is the type of diet. The meta-
analysis conducted by Meng et al 2011[19], showed that in comparation with the clear liquid 
diet, the early oral refeeding with a solid diet might provide better outcomes and is safe for 
patients with AP. Based on these results we started with a solid diet in both groups, so the 
diet type did not influence the results of the study, and shows that this type of diet can be 
started without complications. 
Masayasu H et al 2016 [20] in a systemic review and meta-analysis reported that early oral 
refeeding reduces the hospital stay length without significant differences in adverse events. 
In our study, the hospital stay was shorter for the EOR group 5 vs 8 days (p= 0.042), this also 
led to the lower hospital cost in the EOR group 2089 vs 3310 dollars (p= 0.0235), this cost 
represents total hospital stay expenses. The results of this study might impact treatment 
strategy and potentially reduce the cost of hospitalization in these patients.  
Eckerwall GE 2007 [11], analyzed the recurrence and systemic inflammatory response, 
measured values of pancreatic-specific amylase serum levels and CRP concentrations, there 
observed any significant difference between groups in any of those biochemical markers for 
amylase of systemic inflammatory response for any days evaluated. In our study we 
measured lipase serum levels and leukocytes as parameters of recurrence and systemic 
inflammatory response; we found that the beginning of the OR did not influence the 
modification of these parameters, so it did not affect the natural history of the disease. 
The strengths of this study were that all patients had the same cause of acute pancreatitis 
(biliary), had at least 24 h of evolution and everyone started orally with the same type of diet, 
that confers homogeneous groups. Another strength is the clear and objective criteria for start 
the diet.  

A limitation of the present study is that design did not include blinding. The nature of the 
intervention (EOR vs UOR) make it obvious that the patients and medical staff are informed 
of the groups. Another limitation was the use of leukocytes but not CRP as marker of 
systemic inflammatory response.  
 
CONCLUSION 
The early oral refeeding is safe in mild acute pancreatitis patients, without adverse 
gastrointestinal events, and reduce the hospital stay and cost compared with usual oral 
refeeding.  
 
 
Abbreviations 
Acute pancreatitis (AP) 
Oral Refeeding (OR) 
Early oral refeeding (EOR) 
Usual oral refeeding (UOR) 
Visual analogue scale (VAS) 
Neil per oral (NPO) 
 
Declarations 
Ethical approval and consent to participate 
This clinical trial was approved by local committee in clinical research and ethics 
committee: Instituto Mexicano del Seguro Social. Coordination of investigation in health.  
Trial registration:  Local Committee 1001 registration number 17 CI 11020146 
COFEPRIS. Trial registration number R-2018-1001-074 August 28, 2018. 
Approval of all participating local hospital boards has been obtained 
 
Consent for publication 
According to the study publication 
 
Availability of data and materials. 
Database available for review 
 

Competing interests 
The authors declare that they have not competing interest 
 
Acknowledgements 
Not applicable 
 
Funding 
Not applicable 
 
Authors ‘contributions 
Author information 
Affiliations 
1. Departament of surgery and clinical research, Hospital Regional de Alta 
Especialidad del Bajío, León Guanajuato, México. 
o Edgard Efrén Lozada Hernández 
o Evelia Apolinar Jiménez 
2. Departament of Surgery, Unidad Médica de Alta Especialidad Bajío, Instituto 
Mexicano del Seguro Social. León, Guanajuato, México 
o Omar Barrón González 
o Santa Vázquez Romero 
o Martin Cano Rosas 
Contributions 
EELH, the lead author, designed the study. OBG conducted all the interviews and alongside 
EELH, undertook the thematic analysis; EAJ, SVR, MCR took part in the schematic 
analysis. All authors have provided input into drafts of this article. All authors had full 
access to all the data in the study and had final responsibility for the decision to submit for 
publication. All authors have read and approved the manuscript in its final state. 
Corresponding author 
Correspondence to Edgard Efren Lozada Hernandez 
 
Author Information 
 
Edgard Efren Lozada Hernandez 
General Surgeon 
Specialist in statistical methods 

Master in clinical research 
Research Director HRAE, UNAM, Mexico 
Associate prosecutor of the course of general surgery HRAEB, UNAM 
 
Correspondence to: edgardlozada@hotmail.com 
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