Lactated Ringer's Versus Normal Saline in the Management of Acute Pancreatitis
Phase: NA
Conditions: Pancreatitis, Acute
Sponsor: University of Southern California

 
Version date: 7/11/18 
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PROTOCOL NUMBER:  
HS-18-00133  
 
 
TITLE:   
Lactated Ringer’s Versus Normal Saline in the 
Management of Acute Pancreatitis 
 
 
 
 
STUDY PHASE:  
Randomized Trial 
 
 
 
STUDY ARMS:  
Lactated Ringer’s Fluid Therapy, Normal Saline Fluid 
Therapy 
 
 
 
IND OR IDE #: 
N/A 
 
 
PRINCIPAL INVESTIGATOR: 
NAME:    
JAMES BUXBAUM MD  
CHIEF OF ENDOSCOPY LAC 
ADDRESS:  
D & T BUILDING, ROOM B4H100  
1983 MARENGO AVE 
LOS ANGELES, CA, 90033-1370 
 
TELEPHONE:  
323 4095371  
 
 
 
 
CO-INVESTIGATOR:  
 
 
 
 
SPONSOR:  
None 
 
 
PARTICIPANTS/LOCATONS:  
LOS ANGELES COUNTY HOSPITAL 
 
 
 
AMENDMENTS/REVISIONS: 
 
 
 
 
 
 
 
 
********************************************************************************** 
********************************************************************************** 

 
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TABLE OF CONTENTS 
 
 
SCHEMA, SYNOPSIS, OR STUDY SUMMARY 
 
 
 
 
 
PAGE 
 
1.0 
BACKGROUND AND HYPOTHESES  
_____ 
 
2.0 
OBJECTIVES AND PURPOSE 
_____ 
 
3.0 
STUDY DESIGN  
_____ 
 
4.0 
DRUG/DEVICE INFORMATION 
_____ 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
_____ 
 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
_____ 
 
7.0  
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY      
 
MANAGEMENT PLAN 
_____  
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
_____  
 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
_____ 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS  
 
_____  
 
11.0 
SPECIAL INSTRUCTIONS  
 
 
 
 
 
 
_____ 
 
12.0 
DATA COLLECTION AND MONITORING 
_____ 
 
13.0 
STATISTICAL CONSIDERATIONS  
_____ 
 
14.0 
REGISTRATION GUIDELINES  
_____ 
 
15.0 
BIOHAZARD CONTAINMENT 
_____ 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
_____ 
 
17.0 
REFERENCES 
 
 
 
 
 
 
 
 
_____ 
 
APPENDICES 
 
 

 
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Association 2018 Acute Pancreatitis Guidelines explicitly state that “The AGA makes no 
recommendation whether normal saline or Ringer’s lactate is used.” A larger trial is needed to 
show whether lR results in a clinically meaningful reduction in SIRS. 
 
2.0 
OBJECTIVES AND PURPOSE 
 
 
To assess the comparative efficacy of normal saline versus lactated ringer’s solution in the 
management of acute pancreatitis.  
 
3.0 
STUDY DESIGN 
 
Patients presenting to the Los Angeles County Hospital with acute pancreatitis are the focus 
population of this study. Pancreatitis will be diagnosed using 2 of 3 criterion; amylase or lipase 
greater than 3 times the upper limit of normal, classic epigastric abdominal pain, and imaging 
consistent with acute pancreatitis.  
 
Patients will be randomized to fluid resuscitation with NS or LR within 8 hours of diagnosis of 
pancreatitis. The inclusion and exclusion criterion will be assessed (see below). Randomization 
will be performed using a random sequence algorithm with concealed allocation. The amount of 
fluids and intervention performed in the emergency department prior to randomization will be 
recorded but not impact randomization strategy.  
 
The patients will be blinded to allocation by covering the bag with an opaque covering. A study 
physician determining the outcomes (see below) will also be blinded. 
 
Following randomization, the volumes of fluid administered for the resuscitation will be 
determined by a pre-determined algorithm that will be the same for both treatment arms. As 
described in the Introduction (Section 1.0) we previously demonstrated in a randomized controlled 
trial that this volume of intravenous hydration hastens clinical recovery and was not associated 
with adverse events.4 The aim of this study is not to study volume but type of fluid used in actue 
pancreatitis.4 Thus patients being managed with both intravenous NS and LR will receive the same 
volume per the algorithm in our prior publication and which is similar to the paradigm used in 
other trials of fluid therapy in pancreatitis.4, 11 Our approach to hydration volume and titration also 
accords with the 2018 recommendations of the American Gastroenterology Association for the 
management of acute pancreatitis.6 
 
The hydration algorithm is as follows: all patients will receive a bolus of the treatment fluid (NS 
versus LR) at a rate of 5 mL/kg/hour to be administered over the first two hours (total 10 mL/kg) 
with an assessment for volume overload at 1 hour. They will then receive maintenance fluids at a 
rate of 3 mL/kg/hour.  
 
After 12 hours participants will have blood urea nitrogen (BUN) assessed, which is part of the 
standard clinical procedure. Those who do not have a fall in this parameter or who develop SIRS 
by this 12 hour checkpoint will receive a second 5 mL/kg/hour bolus over two hours (as above) of 
their designated treatment fluid followed by further treatment fluid at a rate of 3 mL/kg/hour. 
Those who do have a fall in BUN will receive further treatment fluid at a rate of 3 mL/kg/hour for 
12 additional hours. The fluid resuscitation strategy based on the 12 hours checkpoint was utilized 
in our prior RCT with good safety and efficacy data as well as the prior randomized trial reported 
by Wu et al.4, 11   
 

 
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Patients’ volume status will be assessed in the following manner: study physicians will perform a 
targeted physical exam which will include assessment of JVD, lung auscultation, and monitoring 
for edema Q12 hours for the first 24 hours, then daily for the remainder of the hospital admission. 
In elderly patients and those with co-morbidities, the targeted physical exam will be performed 
Q12 hours for the entire hospital admission. Vitals will also be obtained Q6-8 hours. If they 
develop signs of fluid overload including pitting edema, ascites, anasacra, pulmonary edema, or 
dyspnea, or signs of renal failure including oliguria, anuria, or hypotension, they will have their 
fluid rate managed at the discretion of their treating physicians. However, it will be requested that 
if further fluid is given that it be the assigned type (LR versus NS). 
 
At 24 hours patients will be assessed for SIRS development (see outcomes). Beyond this point 
fluid rate will be per the primary team though it still be encouraged that the assigned type of fluid 
(LR versus NS) is used for additional resuscitation with the rate and volume beyond this point at 
the discretion of the treating physician. However, if the treating physicians have a strong 
preference to change to a different fluid  type for clinical reasons this will be recorded (for post hoc 
analysis) and the patient included in the intentiont to treat analysis.4 
 
Patients will be recruited until the desired sample size is obtained (see Statistical Considerations), 
which is expected to occur over 12 months.  
 
 
 
4.0 
DRUG/DEVICE INFORMATION 
 
 
Not applicable 
 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
5.1 
Inclusion Criteria:   
 
Presentation with acute pancreatitis as defined by two of three criterion; amylase or lipase > 3x the 
upper limit of normal, classical abdominal pain, or imaging suggestive of pancreatitis. Such 
radiographic findings include swelling, edema, or heterogeneity of the gland or peripancreatic fluid 
or stranding.12 
 
 
5.2 
Exclusion Criteria 
 
 
Patients with severe pancreatitis as defined by the Revised Atlanta Classification will be 
excluded.13 We are excluding those with severe disease as these patients require highy specified, 
individualized fluid protocols. Severe pancreatitis is defined by the Revised Atlanta Classification 
as those with a Modified Marshall score of >2 for their cardiovascular renal, or respiratory system 
will be excluded (Figure 2).13   Practically this includes patients with systolic blood pressure <90, 
serum creatinine >1.9, and PaO2/FiO2 <300 (Figure 3). Since blood gases are unlikely to be drawn 
on those with mild pancreatitis we will exclude patients with an oxygen saturation <92% on room 
air and certainly any patients which require intubation for respiratory failure due to pancreatitis. 
 
Figure 2: Modified Marshall Score used for Revised Atlanta Criterion Definition of Severe 
Pancreatitis (Reference 13) 

 
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6.3 
There will be a randomization of patients to NS versus LR fluids groups in 1:1 allocation 
ratio. Randomization will be performed by the SC-CTSI Bioinformatics and Bioinformatics 
Group. 
 
 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND  
 
TOXICITY MANAGEMENT PLAN 
 
 
 
Not applicable 
 
 
 
7.2 Drug studies: Not applicable 
 
 
Criteria for removal from treatment   
 
7.3.1 Patients who develop a complication of the study, namely fluid overload will be withdrawn 
from the treatment protocol but not the study, and will have their fluid rates managed by their 
treating physicians.  These patients have met the secondary outcome of fluid overload. 
 
7.3.2 Patients who develop renal failure or severe pancreatitis will also be withdrawn from the 
treatment protocol but not the study, and their fluid rates will be managed at the discretion of their 
treating physicians. 
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
 
 
8.1 
Side effects/Toxicities to be monitored. 
 
 
 
 
8.1.1  
Fluid overload including pitting edema, ascites, anasacra, pulmonary edema, or dyspnea is 
the primary side effect of the treatment.   
 
8.1.2 
Electrolyte abnormalities, including hyperchloremia, metabolic acidosis, and hyponatremia 
are potential side effects of the fluids administered. 
 
 
 
 
8.1.3  
Long-term toxicities to be monitored after completion of therapy: There are no foreseeable 
long-term effects of the study fluids. 
 
 
********************************************** 
 
8.2 
Adverse Event Reporting:  
 
 
 
 
 
8.3.1 Type of event to be reported and timing of reports. 
 
If patients develop fluid overload including pitting edema, ascites, anasacra, pulmonary 
edema, or dyspnea they will be removed from the treatment protocol and be managed at the 
discretion of their treating physicians. This will be reported to the principal investigators 
and will be reviewed by the study team as well as two staff physicians in the 

 
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gastroenterology division who are not part of the study team. This will also be reported to 
the IRB. 
 
If patients experience any further events that are detected on telephone call follow-up these 
will be coded as A) related to study or B) not related to the study. Their severity and A) 
whether they were expected or B) not expected will also be recorded. These complications 
will also be reported to the principal investigators and will be reviewed by the study team as 
well as two staff physicians in the gastroenterology division who are not part of the study 
team. They will also be reported to the IRB. 
 
8.32 
Places for submitting reports:  IRB, Sponsor, Investigational Drug Branch, etc. 
 
 
 
Adverse events will be reported to the IRB and data safety monitoring committee. 
 
 
 
8.4 
Data Monitoring Committee  
 
The data safety monitoring committee will include the principal investigators from 
medicine/gastroenterology and surgery as well as the entire study team. An outside senior 
physician from gastroenterology or surgery will also be asked to participate. Meetings will 
occur every 3 months. 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
 
 
Parameter 
Admisson 12 
24  
hours 
Daily in 
hospital 
Follow up 
phone call 2 
weeks 
Comprehensive History & 
Complete Physical  
  Examination 
X 
 
 
 
 
Targeted History & Physical 
Examination  
 
X 
X 
X 
 
Targeted History 
 
 
 
 
X 
Metabolic panel-part of standard 
of care for pancreatitis 
X 
X 
 
 
 
 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
 
Endpoint Definitions 
 
Primary Outcome will be the  change in SIRS prevalence from enrollment to 24 hours. 
SIRS will be defined as 2/4 criterion14 
 
a) HR >90 
 
b) RR >20 or paCO2 <32 on room air 

 
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c) T >100.4 F <96.8 F 
 
d) WBC >12, <4 or >10%  
 
Secondary Outcomes  
1) Change in SIRS prevalence from enrollment to 48 hours and 72 hours.  
2) Moderately severe acute pancreatitis will be defined if at least 1 of the criterion is present16 
1. Organ failure that resolves within 48h (transient organ failure) 
2. Local or systemic complications without persistent organ failure 
 
3) Severe acute pancreatitis will be defined as persistent organ failure (>48 hrs)16. 
4) Change in PASS Score from enrollment to 24, 48, and 72 hours17.  
5) ICU admission as well as ICU intervention including intubation, respiratory distress without intubation 
defined as RR>20 AND O2 Sat<90% on room air, death, development of extrapancreatic fluid collection 
(EPFS) will also be secondary outcomes. 
6) Length of hospitalization  
7) Persistent pain or disability after discharge as well as time to return to work will be recorded by a 2 
week follow up phone call. 
8) Time to advancement of oral diet and discharge will also be secondary outcomes.  
 
11.0 
SPECIAL INSTRUCTIONS: 
 
 
Not applicable  
 
12.0 
DATA COLLECTION AND MONITORING 
 
SEE ATTACHED INITIAL, INTERVAL, AND TELEPHONE COLLECTION FORM. In 
collaboration with Southern California Clinical and Translational Science Institute (SC CTSI), a 
(Research Electronic Data Capture) REDCap database
1 will be developed and utilized for this 
study. REDCap is a secure, web-based application designed to support data capture for research 
studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data downloads 
to common statistical packages; and 4) procedures for importing data from external sources
2. 
Provision of data to IRB, NIH, and FDA is facilitated by this database system.  
 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
 
 
13.1 
 
 
 
Descriptive statistics will be performed for each group (LR versus NS) and comparisons 
made to determine if the groups are balanced by patients’ characteristics and various 
pertinent features such as type of pancreatitis. Intent-to-treat analysis of the primary 
outcome will be achieved using logistic regression models to assess whether there is a 
difference in SIRS prevalence at at 24 hours, adjusting for presence of SIRS at baseline. 
The odds of SIRS in the LR group compared with the NS group will be reported to assess 
clinical effectiveness of LR versus NS. We will also examine SIRS components 
independently using this same method. Dichotomous secondary outcomes will use this 
method, while length of hospitalization and time  to advancement of oral diet and discharge 

 
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will be analyzed using cox proportional hazard regression models. Analyses will be 
performed using SPSS (V.24), and a priori a = 0.05.   
 
 
 
 
 
 
 
As described in the introduction one small RCT showed an 83% greater reduction in SIRS 
prevalence for LR relative to NS at 24 hours and the other showed no significant 
reduction.10-11  
 
Thus we based our calculation on the known LAC+USC SIRS prevalence for patient s 
managed with NS (our sampling population) and the decrease in SIRS prevalence which 
would be defined as clinically significant.15 
 
 
 
We used G*Power to estimate a priori sample size for SIRS estimating a prevalence of 
SIRS of 50% for NS  (a = 0.05, two sided; 1-b = 0.80) based on our published large 
observational cohort of patients with acute pancreaititis at LAC+USC.15 
Based on discussion with experts we defined a clinically significant reduction of SIRS 
prevalance of LR of 50% relative to NS.  Our proposed sample size of 119 will allow us to 
detect a clinically significant difference in SIRS prevalence at 24 hours between LR and NS 
 
14.0 
REGISTRATION GUIDELINE 
 
 
14.1 
Phone number to register the patients.   
323 409 5371 
 
 
14.2 
Forms and records needed for registration:  Informed Consent, Registration/Eligibility 
Worksheet, Flow Sheet, etc.   
 
 
 
SEE ATTACHED INITIAL COLLECTION FORM AND INFORMED CONSENT FORM 
 
 
  
 
15.0 
BIOHAZARD COMTAINMENT 
 
 
 
Not applicable 
 
 
 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
All institutional and Federal regulations concerning the Informed Consent form will be fulfilled.  
The study will be conducted in adherence to ICH Good Clinical Practice. 
 
 
17.0 
REFERENCES 
 
1. 
Tenner S, Baillie J, DeWitt J, Vege SS. American College of Gastroenterology guideline: 
management of acute pancreatitis. The American journal of gastroenterology 2013;108:1400-15; 16. 

 
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2. 
Singh VK, Gardner TB, Papachristou GI, et al. An international multicenter study of early 
intravenous fluid administration and outcome in acute pancreatitis. United European gastroenterology 
journal 2017;5:491-8. 
3. 
Forsmark CE, Swaroop Vege S, Wilcox CM. 
4. 
Buxbaum JL, Quezada M, Da B, et al. Early Aggressive Hydration Hastens Clinical Improvement 
in Mild Acute Pancreatitis. Am J Gastroenterol 2017;112:797-803. 
5. 
Cuthbertson CM, Christophi C. Disturbances of the microcirculation in acute pancreatitis. The 
British journal of surgery 2006;93:518-30. 
6. 
Crockett S, Falck-Ytter Y, Wani S, Gardner TB. Acute Pancreatitis Guideline. Gastroenterology 
2018;154:1102. 
7. 
Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and 
network meta-analysis. Annals of internal medicine 2014;161:347-55. 
8. 
Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory 
response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004;286:R686-
92. 
9. 
Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer's solution reduces systemic inflammation 
compared with saline in patients with acute pancreatitis. Clinical gastroenterology and hepatology : the 
official clinical practice journal of the American Gastroenterological Association 2011;9:710-7.e1. 
10. 
de-Madaria E, Herrera-Marante I, Gonzalez-Camacho V, et al. Fluid resuscitation with lactated 
Ringer's solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. United 
European Gastroenterol J 2018;6:63-72. 
11. 
Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer's solution reduces systemic inflammation 
compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710-7 e1. 
12. 
Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology 
2002;223:603-13. 
13. 
Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: revision of the 
Atlanta classification and definitions by international consensus. Gut 2013;62:102-11. 
14. 
Warndorf MG, Kurtzman JT, Bartel MJ, et al. Early fluid resuscitation reduces morbidity among 
patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:705-9. 
15. 
Buxbaum J, Quezada M, Chong B, et al. The Pancreatitis Activity Scoring System predicts clinical 
outcomes in acute pancreatitis: findings from a prospective cohort study. Am J Gastroenterol 
2018;113:755-64.