Effect of Early Weight-based Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: an Open-label Multicenter Randomized-controlled Trial
Phase: PHASE3
Conditions: Acute Pancreatitis
Sponsor: Enrique de-Madaria

STUDY PROTOCOL
published: 02 September 2020
doi: 10.3389/fmed.2020.00440
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September 2020 | Volume 7 | Article 440
Edited by:
Guru Trikudanathan,
Medical School, University of
Minnesota, United States
Reviewed by:
John Windsor,
The University of Auckland,
New Zealand
Giuseppe Losurdo,
University of Bari Medical School, Italy
*Correspondence:
Enrique de-Madaria
enriquedemadaria@gmail.com
Specialty section:
This article was submitted to
Gastroenterology,
a section of the journal
Frontiers in Medicine
Received: 05 May 2020
Accepted: 06 July 2020
Published: 02 September 2020
Citation:
Bolado F, Buxbaum JL,
Vaillo-Rocamora A, Cárdenas-Jaén K,
Maisonneuve P and de-Madaria E
(2020) Early Weight-Based Aggressive
vs. Non-Aggressive Goal-Directed
Fluid Resuscitation in the Early Phase
of Acute Pancreatitis: An Open-Label
Multicenter Randomized Controlled
Trial (The WATERFALL Trial), Design,
and Rationale. Front. Med. 7:440.
doi: 10.3389/fmed.2020.00440
Early Weight-Based Aggressive vs.
Non-Aggressive Goal-Directed Fluid
Resuscitation in the Early Phase of
Acute Pancreatitis: An Open-Label
Multicenter Randomized Controlled
Trial (The WATERFALL Trial), Design,
and Rationale
Federico Bolado 1, James L. Buxbaum 2, Alicia Vaillo-Rocamora 3, Karina Cárdenas-Jaén 3,
Patrick Maisonneuve 4 and Enrique de-Madaria 3*
1 Gastroenterology Department, Complejo Hospitalario de Navarra, Pamplona, Spain, 2 Division of Gastrointestinal and Liver
Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States, 3 Gastroenterology
Department, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante,
Spain, 4 Division of Epidemiology and Biostatistics, IEO-Istituto Europeo di Oncologia IRCCS, Milan, Italy
Treatment options are limited for acute pancreatitis (AP). Early aggressive ﬂuid
resuscitation (AFR) has been widely considered beneﬁcial because of theoretical
improvement in end-organ perfusion, including the pancreas and gut, with pancreatic
necrosis and bacterial translocation as consequences of ischemia. There is scarce
direct evidence for its association to improved outcomes. Furthermore, it has been
described that AFR may be associated with poor outcomes in severe AP. WATERFALL
is an investigator-initiated international multicenter open-label randomized controlled trial
comparing AFR vs. moderate ﬂuid resuscitation (MFR) in AP. The main outcome variable
will be the incidence of moderate to severe AP (a clinically relevant outcome that has
been validated). Aggressive ﬂuid resuscitation will consist in lactated Ringer solution
(LR) 20-mL/kg bolus (administered over 2 h) followed by LR 3 mL/kg per hour. Patients
randomized to MFR will receive an LR bolus 10 mL/kg in case of hypovolemia or no
bolus in patients with normal volemia, followed by LR 1.5 mL/kg per hour. The patients
will be assessed at 3 (±1), 12 (±4), 24 (±4), 48 (±4), and 72 (±4) h from recruitment, and
ﬂuid resuscitation will be adjusted to the patient’s clinical and analytical status according
to a protocol. Based on a prospective multicenter study, the incidence of moderate to
severe AP is 35%. Sample sizes of 372 patients per group (overall 744) achieve 80%
power to detect a difference in the incidence of moderate to severe AP of 10%, at a
signiﬁcance level (α) of 0.05 using a two-sided z-test, assuming a 10% dropout rate.
These results assume that three sequential tests are made using the O’Brien–Fleming
spending function to determine the test boundaries.
Keywords: ﬂuid resuscitation, ringer lactate, ﬂuid therapy, acute pancreatitis (AP), randomized controlled
(clinical) trial

Bolado et al.
Fluid Resuscitation in Acute Pancreatitis
INTRODUCTION
Acute
pancreatitis
(AP)
is
the
third
leading
cause
of
hospital admission for gastrointestinal disease (1). While
the majority of patients with AP have a mild course, 35%
develop moderate to severe disease, which is associated
with high morbidity and an increased risk of mortality
(2). Thus, a vital aim in the early management of AP is
to decrease the incidence of moderate to severe disease.
Unfortunately,
there
are
currently
no
speciﬁc
therapies
for AP, so the cornerstone in the management of this
frequent
disease
is
supportive
treatment,
including
ﬂuid
resuscitation,
analgesia,
and
close
monitoring
for
organ
failure (3).
Since late 1990s, experts have recommended aggressive
ﬂuid resuscitation (AFR) in AP (4) based on an observed
correlation
between
hemoconcentration
and
necrosis
(5).
Aggressive
ﬂuid
resuscitation
became
a
dogma
in
pancreatology, but it was based on retrospective studies at
high risk of biases (6). In 2011, a prospective cohort study
suggested that AFR was associated with poor outcomes in
AP (7). In 2017, an international multicenter observational
study of more than 1,000 patients reported that there was
not a clear correlation between early AFR and improved
outcomes (8).
Randomized controlled trials (RCTs) of ﬂuid resuscitation
for AP have been limited by small sample sizes and ﬂawed
design. Two small RCTs from the same group from China
described that patients with severe AP had unfavorable
outcomes including higher mortality rate in the context
of AFR (9, 10). Another study by Buxbaum et al. (11)
in the United States suggested that AFR hastens clinical
improvement among patients with predicted mild AP, but
was not powered to address clinically important outcomes,
such as the development of organ failure (12). Moderate to
severe AP as deﬁned by the revised Atlanta classiﬁcation
(13) has been validated as a clinically relevant outcome
variable in several studies, including our nationwide Spanish
multicenter prospective cohort study involving more than 1,600
patients (2).
Few
RCTs
on
AP
have
taken
into
account
patient
symptoms. PAN-PROMISE is a recently validated patient-
reported outcome measurement scale for AP (14), thus
making possible to know the impact of this disease on
patients’ wellness.
An adequately powered RCT focused on clinically relevant
outcome variables and taking into account the patients’
perspective is needed to deﬁne the appropriate ﬂuid strategy
in AP.
Abbreviations: AEG, Spanish Association of Gastroenterology; AESPANC,
Spanish Association of Pancreatology; AFR, aggressive ﬂuid resuscitation;
AP, acute pancreatitis; ARDS, acute respiratory distress syndrome; AUGH,
Alicante University General Hospital; BUN, blood urea nitrogen; DSMB,
Data and Safety Monitoring Board; eCRF, electronic case report form;
ICU, intensive care unit; LR, lactated Ringer solution; MFR, moderate ﬂuid
resuscitation; RCT, randomized controlled study; SIRS, systemic inﬂammatory
response syndrome.
METHODS AND ANALYSIS
Design
WATERFALL
is
an
investigator-initiated
international
multicenter open-label RCT comparing early AFR vs. moderate
ﬂuid resuscitation (MFR). The study is endorsed by the Spanish
Association of Pancreatology (AESPANC) and the Spanish
Association of Gastroenterology (AEG). This trial protocol
follows the Standard protocol items: recommendations for
interventional trials (SPIRIT) guidelines (15) (Figure 1).
Population
Consecutive
patients
with
clinical
suspicion
of
AP
in
the emergency room of any of the collaborating centers
(Supplementary Material 1) will be evaluated to participate in
the study.
Inclusion Criteria
(1) Patients 18 years or older
(2) Diagnosis of AP according to the revised Atlanta classiﬁcation
(13), which requires two of the following three criteria: (A) typical
abdominal pain, (B) increase in serum amylase or lipase levels
higher than three times the upper limit of normality, and (C)
signs of AP in imaging.
Exclusion Criteria
Patients will be excluded if they fulﬁll any of the following criteria:
(1) Uncontrolled arterial hypertension (systolic blood pressure
>180 and/or diastolic blood pressure >100 mmHg)
(2) New York Heart Association class II heart failure (slight
limitation of physical activity; fatigue, palpitations, or dyspnea
with ordinal physical activity) or worse, or ejection fraction
<50% in the last echocardiography
(3) Decompensated cirrhosis (Child’s class B or C)
(4) Hyper or hyponatremia (<135 or >145 mEq/L)
(5) Hyperkalemia (>5 mEq/L)
(6) Hypercalcemia
(albumin
or
protein-corrected
calcium
>10.5 mg/dL)
(7) Baseline kidney failure (basal glomerular ﬁltration rate <60
mL/min per 1.73 m2)
(8) Clinical signs or symptoms of volume overload or heart
failure at recruitment (dyspnea, peripheral edema, pulmonary
rales, or evident increased jugular ingurgitation at 45◦)
(9) Shock or respiratory failure according to the revised Atlanta
classiﬁcation at recruitment (non-ﬂuid-responding systolic
blood pressure <90 mmHg, PaO2/FIO2 ≤300)
(10) Time from pain onset to arrival to emergency room >24 h
(11) Time from conﬁrmation of pancreatitis to randomization
>8 h
(12) Severe comorbidity associated with an estimated life
expectancy <1 year
(13) Conﬁrmed chronic pancreatitis [in case of recurrent
alcoholic pancreatitis a recent (<6 months) computed
tomography
(CT)
scan/magnetic
resonance
imaging
(MRI) or endoscopic ultrasound is needed to rule out
chronic pancreatitis]
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Fluid Resuscitation in Acute Pancreatitis
FIGURE 1 | SPIRIT scheduled enrollment, interventions, and assessments. *The detailed protocol is illustrated in Figure 2. LR, lactated Ringer. Dashed lines stands
for optional, according to patient status.
Recruitment, Randomization, and Data
Acquisition
Recruitment
will
be
performed
by
collaborating
gastroenterologists and/or surgeons of the participating centers.
Patients who meet the eligibility criteria will be randomly
assigned to AFR or MFR after informed consent. The electronic
case report form (eCRD) will be based on RedCAP web-based
application (16) (AEG node). Randomization will be performed
automatically by REDCap, stratiﬁed by center, presence of
systemic inﬂammatory response syndrome (SIRS), and suspected
baseline hypovolemia (see below).
Treatment Protocol
1. Deﬁnitions
Fluid overload:
Fluid overload is deﬁned by the presence of at least two
of the following three criteria (adapted from Sharma et al.
deﬁnition of heart failure) (17):
Criteria 1. Hemodynamic-imaging evidence (≥1):
- Non-invasive diagnostic evidence of heart failure [i.e.,
echocardiographic, cardiac (MRI)]
- Radiographic evidence of pulmonary congestion
- Invasive cardiac catheterization suggesting evidence of
heart failure [i.e., pulmonary capillary wedge pressure
(or left ventricular end-diastolic pressure) >18 mmHg,
right arterial pressure [or central venous pressure] >12
mmHg, or cardiac index <2.2 L/min per m2]
Criteria 2. Heart failure symptoms (1):
- Dyspnea
Criteria 3. Heart failure signs (≥1):
- Peripheral edema
- Pulmonary rales or crackles, or crepitation
- Increased jugular venous pressure, hepatojugular reﬂux,
or both
Additionally, in those with suspected ﬂuid overload, acute
respiratory distress syndrome (ARDS) must be ruled out.
Exclusion of ARDS for this may be met by one of
two criteria:
(1) Prompt
response
to
diuretics
and/or
decrease
in
ﬂuid resuscitation volume rate and/or hemodialysis-
hemoﬁltration
(2) Absence of ARDS criterion (for ARDS, the patient must
meet all the following four criteria as deﬁned by the
modiﬁed Berlin deﬁnition, ARDS Deﬁnition Task Force,
JAMA 2012)
(A) Onset within 1 week of the pancreatitis
(B) Bilateral opacities not fully explained by eﬀusions, lobar
collapse, or nodules
(C) Respiratory failure not fully explained by cardiac
failure or ﬂuid overload needs objective assessment (i.e.,
echocardiography) to exclude hydrostatic edema if no risk
factor is present
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FIGURE 2 | Detailed treatment protocol.
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Fluid Resuscitation in Acute Pancreatitis
(D) PaO2/FIO2 ≤300
Severity of ﬂuid overload will be classiﬁed into three categories:
– Mild: Patients respond to medical treatment or decrease
in volume infusion rate, and the PaO2/FIO2
never
decreases <300.
– Moderate: Patients respond to medical treatment or
decrease in volume infusion rate and have at least one
measurement with PaO2/FIO2 <300.
– Severe:
Patients
require
invasive
or
non-invasive
mechanical ventilation, and/or hemoﬁltration, or expire
due to overload. It is crucial to rule out ARDS in this
scenario (see above).
Hypovolemia:
Hypovolemia is deﬁned by the presence of one criterion
or more:
(1) Baseline creatinine >1.1 mg/dL or blood urea nitrogen
(BUN) >20 mg/dl, equivalent to urea >43 mg/dL
(2) Hematocrit >44%
(3) Increase in creatinine and/or BUN and/or urea from the
previous value
(4) Urine output <0.75 mL/kg per hour
(5) Systolic blood pressure <90 mmHg without other
explanation than hypovolemia
(6) Signs and/or symptoms of dehydration (intense thirst,
dehydrated oral mucosa, decreased skin turgor–skin pinch
Systemic inﬂammatory response syndrome:
Systemic inﬂammatory response syndrome will be deﬁned
by the presence of two or more of the following criteria:
(1) Leukocyte count <4,000 or >12,000/mm3
(2) Heart rate >90/min
(3) Respiratory rate >20 breaths/min or PCO2 <32 mmHg
(4) Temperature (Celsius) <36 or >38◦C
Criteria to start oral feeding
Feeding “per os” will be initiated when:
(A) The intensity of abdominal pain is <5 over 10 (0 =
absence of pain and 10 = maximum possible pain); and
(B) The patient feels that he/she can tolerate oral feeding
2. Treatment Arms
All patients included in the study will be randomly assigned
to group AFR or MFR.
Group AFR (See Flowchart in Figure 2)
Patients randomized to AFR will receive a 20-mL/kg bolus of
lactated Ringer solution (LR) administered over 2 h, followed
by an infusion at 3 mL/kg per hour. Fluid overload will be ruled
out at 3 ± 1 h after randomization. Afterward, there are four
checkpoints: 12 (±4), 24 (±4), 48 (±4), and 72 (±4) h after
randomization. On each of them, criteria for hypovolemia,
ﬂuid overload, and for oral feeding are checked. According to
the patient status:
(A) If no ﬂuid overload or hypovolemia criteria are met, the
LR infusion rate will be reduced to 1.5 mL/kg per hour.
(B) If criteria for ﬂuid overload but no hypovolemia are met,
the infusion rate of LR will be decreased or stopped, and if
needed, the study physicians will consider diuretics and/or
O2 as well as electrocardiogram chest X-ray and blood gases
according to their clinical judgment. In case of refractory
signs/symptoms of ﬂuid overload, intensive care unit (ICU)
assessment will be obtained.
(C) If criteria for hypovolemia without ﬂuid overload are met,
a bolus of LR 20 mL/kg over 2 h will be given followed by an
infusion of LR 3 mL/kg per hour. One or more additional
20-mL/kg boluses may be given prior to the 24-h checkpoint
only in case of urine output <0.5 mL/kg per hour or
hypotension (systolic blood pressure <90 mmHg). In case
of refractory hypotension, ICU assessment will be obtained.
(D) If ﬂuid overload and hypovolemia criteria are both
met, management should be performed according to
the physician clinical judgment; in diﬃcult cases, ICU
assessment will be obtained.
Fluid resuscitation will be stopped at 48 h after randomization
or later in patients without hypovolemia, tolerating oral
feeding for at least 8 h. Lactated Ringer solution infusion
should be maintained in case of hypovolemia or intolerance
to oral feeding. Recommendations for enteral nutrition are
explained bellow (general management).
Group MFR (See Flowchart in Figure 2)
Group MFR will receive an LR infusion at 1.5 mL/kg per hour.
A prior LR bolus of 10 mL/kg over 2 h should be administered
only if criteria for hypovolemia are found. Fluid overload will
be ruled out at 3 ± 1 h after starting the study treatment.
Afterward, following the same checkpoints than in group AFR,
patient management is as follows:
(A) If no ﬂuid overload or hypovolemia criteria are met,
LR infusion will be continued at 1.5 mL/kg per hour and
criteria to start oral feeding will be assessed. After 8 h
tolerating oral feeding, the LR infusion can be stopped.
(B) If ﬂuid overload but not hypovolemia criteria are met,
the infusion rate of LR will be decreased or stopped, and if
needed, the study physicians will consider diuretics and/or
O2, as well as electrocardiogram chest X-ray and blood
gases if necessary according to their clinical judgment.
Patients will be evaluated for criteria to start oral feeding.
In case of refractory signs/symptoms of ﬂuid overload, ICU
assessment will be obtained.
(C) If criteria for hypovolemia but not ﬂuid overload are met,
a bolus of LR 10 mL/kg over 2 h will be given followed by
infusion of LR 1.5 mL/kg per hour. One or more additional
10-mL/kg boluses may be given prior to the 24-h checkpoint
only in case of urine output <0.5 mL/kg per hour or
hypotension (systolic blood pressure <90 mmHg). In case
of refractory hypotension, ICU assessment will be obtained.
(D) If ﬂuid overload and hypovolemia criteria are both
met, management should be performed according to
the physician clinical judgment, in diﬃcult cases ICU
assessment will be obtained.
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Bolado et al.
Fluid Resuscitation in Acute Pancreatitis
Thus, in the MFR group, ﬂuid resuscitation can be stopped as
early as 20 h after randomization, if the patient tolerates for 8 h,
oral feeding started at 12 (±4)h.
3. General Management
- Blood test (hematocrit, leukocyte count, BUN, urea, and
creatinine) will be obtained at 12 h (±4), 24 h (±4), 48 h
(±4), and 72 h (±4) in all patients.
- A CT scan is recommended to be performed at least 72 h
after recruitment to those patients with SIRS at emergency
room, with persistent pain (>5 over 10) for more than
48 h, persistent intolerance to oral feeding, C-reactive
protein >150 mg/L at 48 h, or in case of suspicion of
local complications.
- All patients must receive at least potassium 40 mEq/day
unless it is contraindicated.
- In case of diabetes, the use of insulin and dextrose solutions
will be decided by the attending physician. In non-diabetic
patients, dextrose use is discouraged.
- Enteral nutrition can be administered according to the
managing physician judgment. We recommend it in
patients who do not tolerate oral feeding at 72 h from
recruitment. Parenteral nutrition can be used in patients not
tolerating oral or enteral feeding.
Aims
This study aims to compare in patients with AP the eﬀect of an
aggressive vs. a MFR strategy on outcomes.
Endpoints
Main endpoint: Our primary endpoint is to compare the
impact of early and aggressive vs. a moderate, more restrictive
ﬂuid resuscitation on the incidence of moderate to severe
AP according to the revision of the Atlanta classiﬁcation
(13). It includes patients with at least one of the following
three criteria:
- Local complications (acute peripancreatic ﬂuid collections
or
pancreatic
necrosis
or/and
peripancreatic
fat
necrosis); or
- Exacerbation of previous comorbidity; or
- Organ
failure
(modiﬁed
Marshall
classiﬁcation
≥2:
creatinine ≥1.9 mg/dL and/or systolic blood pressure <90
mmHg despite ﬂuid resuscitation and/or PaO2/FIO2 ≤300).
Secondary aims: Additional aims include a comparison of the
following outcomes among the treatment arms:
(A) PAN-PROMISE scale (14) (Table 1) will be obtained at
recruitment, and at 12 h (±4), 24 h (±4), 48 h (±4), and 72 h
(±4) checkpoints
(B) Mortality
(C) Transient
or
persistent
(>48 h)
organ
failure
(cardiovascular, kidney, respiratory) (13).
(D) Local complications (13).
(E) Fluid overload
(F) Length of hospital stay
(G) ICU stay (admission or not, and length of stay)
(H) Need for invasive treatment
(I) Need for nutritional support
(J) Serum C-reactive protein at 48 and 72 h
(K) SIRS criteria at 12, 24, 48, and 72 h. Transient or persistent
(>48 h) SIRS
(L) Combined variable: death and/or persistent organ failure
and/or infection of pancreatic necrosis (18)
Sample Size
The sample size was calculated based on the main endpoint.
Our prior multicenter study indicated a baseline incidence of
moderate to severe AP of 35% (2). Sample sizes of 372 in each
group achieve 80% power to detect a diﬀerence of 10% reduction
between the group incidence of moderate to severe disease (from
35 to 25%) at a signiﬁcance level (α) of 0.05, using a two-sided z
test. We anticipated a dropout rate of 10%. These results assume
that three sequential tests are made using the O’Brien–Fleming
spending function to determine the test boundaries.
Data Analysis
All analyses will be performed on an intention-to-treat basis.
The O’Brien–Fleming test, a multiple-testing procedure using
group-sequential design for two proportions, will be used for
comparing both treatments. The three sequential tests are two
interim analyses and the ﬁnal one. Accordingly, the trial could
be stopped early for eﬃcacy (primary endpoint) if the observed
two-sided P-value is <0.0002 at the ﬁrst interim analysis (after
one-third of patients have been enrolled) or is <0.012 at second
interim analysis (after two-thirds of patients have been enrolled),
favoring AFR. At ﬁnal analysis, the hypothesis that the incidence
of moderate to severe pancreatitis is similar in the two treatment
arms will be rejected if P < 0.046. Estimates were calculated with
the PASS 2008 software (NCSS, LLC. Kaysville, UT, USA).
Descriptive analysis will be expressed in mean (standard
deviation), median (interquartile range), or n (%). Normality
will be assessed by means of the Shapiro–Wilk test. Diﬀerences
in continuous variables between the treatment arms will be
compared by Student t-test or Mann–Whitney U test. Categorical
variables will be compared using χ2 test (with Fisher correction
when needed). Comparison of secondary endpoints will be
expressed in terms of a relative risk and corresponding 95%
conﬁdence intervals. In case of statistically signiﬁcant diﬀerences
in baseline characteristics, a multivariable logistic regression
analysis will be performed to correct it. A two-sided P-value of
TABLE 1 | PAN-PROMISE scale (14).
Each item is scored from 0 to 10. The patient should be asked for the worst
score in the last 24 h (0 = none, 10 = the highest possible intensity)
A. Pain, especially in the abdomen, chest, or back
B. Abdominal distention (bloating, sensation of excess gas)
C. Difﬁculty eating, sensation of food being stuck in the stomach
D. Difﬁculty with bowel movements (constipation or straining on bowel
movements)
E. Nausea and/or vomiting
F. Thirst
G. Weakness, lack of energy, fatigue, difﬁculty moving
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Fluid Resuscitation in Acute Pancreatitis
<0.05 will be considered statistically signiﬁcant. Calculation will
be performed with SPSS 21.0 (IBM, Armonk, NY, USA).
Predeﬁned subgroup analysis will be performed in patients
with and without SIRS at admission, persistent (>48 h) SIRS, and
hypovolemia at admission.
The report of the results will follow the CONSORT
(Consolidated Standards of Reporting Trials) statement (19).
Data and Safety Monitoring Board
The Data
and Safety
Monitoring Board
(DSMB)
is an
independent expert committee in charge of monitoring the data
to guarantee safety of both recruited patients and patients to be
recruited. An initial meeting will take place at the beginning of
recruitment to plan scheduled future meetings. The DSMB will
have access to updated anonymized data stored on the electronic
case report form. The DSMB can advise to stop the study, in case
of clear evidence of eﬃcacy or harm in one treatment arm over
the other, or in case of a slow recruitment rate.
Data and Safety Monitoring Board members are P. Zapater
[Department of Clinical Pharmacology, Alicante University
General
Hospital
(AUGH)
with
experience
in
clinical
trials, statistics, and drug safety], R. Jover (Department of
Gastroenterology, AUGH, with experience in clinical trials
in the gastroenterology ﬁeld), and V. Climent (Department
of
Cardiology,
AUGH,
an
expert
on
heart
failure
and
ﬂuid overload).
Study Duration
The anticipated study duration is 3 years. The DSMB may advise
to halt the study previously due to safety issues or clear evidence
for a more eﬀective treatment arm (as explained in Sample Size,
three analyses will be performed).
DISCUSSION
Acute pancreatitis is a frequent cause of admission, which entails
a signiﬁcant economic burden (1). Some advances have been
made in recent years in understanding the pathophysiology and
severity determinants of this disease, but it still lacks a speciﬁc
treatment. Observational studies showed a close relationship
between hemoconcentration and necrosis and hypothesized that
AFR may prevent pancreatic necrosis by increasing pancreatic
blood ﬂow (5). Furthermore, correcting hypovolemia may
be important for other end organs. Persisting splanchnic
vasoconstriction in response to AP and hypovolemia secondary
to third space ﬂuid loss may be associated with ischemic injury
to the gut and thus to increased intestinal permeability, which
may lead to bacterial translocation and a subsequent SIRS (20).
However, there are no RCTs showing a direct relationship
between AFR and a decrease in local complications. The available
RCT showing beneﬁts for AFR included only predicted mild
AP and used in fact intermediate or surrogate endpoints (11),
as more robust ones are not feasible for a single-center study.
The only RCTs that used robust outcomes were performed on
severe AP and described a deleterious eﬀect of AFR on those
very sick patients (9, 10). WATERFALL aims to compare an
aggressive vs. a restrictive ﬂuid resuscitation strategy. The study
has been designed to detect a decrease on the incidence of
complications in AP and will monitor carefully the incidence of
adverse eﬀects of AFR (ﬂuid overload). Serious concerns have
emerged about the safety of high-dose ﬂuids (7), especially in
patients with comorbidities and elderly patients. WATERFALL
has no age limit for enrolment. Acute pancreatitis incidence
increases with age, so excluding older people would result
in a decreased external validity. A close evaluation of ﬂuid
overload signs and symptoms will be carried out throughout
the study period. As stated above, an independent expert
committee will monitor patients’ safety and might advise to
stop the study if the harms of an arm clearly exceed those of
the other.
One important aspect of WATERFALL will be to explore the
eﬀect of ﬂuid resuscitation on the patient’s symptoms. We may
hypothesize that AFR may be associated with decreased thirst
[an important symptom for patients with AP (14)] but may
increase abdominal distension or even decrease oral tolerance
of food. For these reasons, changes in ﬂuid policy may result
in changes in patients’ wellness. Our study will also focus
on this frequently eluded point, using the PAN-PROMISE
scale, a speciﬁc patient-reported outcome measurement for
AP (14).
TABLE 2 | Rules for authorship and access to the database.
Recruited patients
Rights
Collaborators will be considered as authors depending of the number of patients recruited without missing data:
<6% of the overall number of patients recruited, <42 patients (<14
patients/year) if the study is ﬁnished at 700 patients
Access to data from the same center
One author in collateral studies, no author in the main study
6–10% patients or 42 to 70 if the study is ﬁnished at 700 patients
Access to data from the same center
One author in the main study
>10–15% patients, >70–105 if the study is ﬁnished at 700 patients
Access to data from the same center
Two authors in the main study
Can apply to access to whole database for post-hoc studies
>15% patients, >105 if the study is ﬁnished at 700 patients
Access to data from the same center
Three authors in the main study
Can apply to access to whole database for post-hoc studies
Please note that the scientiﬁc journal may limit the number of authors, in that case we will include as many authors as possible based on the number of patients recruited.
Frontiers in Medicine | www.frontiersin.org
7
September 2020 | Volume 7 | Article 440

Bolado et al.
Fluid Resuscitation in Acute Pancreatitis
Fluid therapy will be based on LR based on its anti-
inﬂammatory eﬀect (21).
WATERFALL
aims
to
include
patients
with
diﬀerent
severity and to have a validated clinically relevant endpoint.
Several studies (2, 22), including a prospective nationwide
study
(2),
have
shown
that
the
diﬀerent
categories
of
severity of the revised Atlanta classiﬁcation are associated
with diﬀerent important outcomes, including hospital stay
and mortality.
In conclusion, WATERFALL aims to answer some vital
clinical questions in AP: does early and AFR with LR improve
relevant endpoints? Is it safe in all patients? Fluid resuscitation
is a widely available, inexpensive therapy. Therefore, the
demonstration of a positive or negative eﬀect of AFR will result
in immediate and important changes in clinical practice.
ETHICS STATEMENT
The study was originally approved on May 29th 2019 by Alicante
University General Hospital (AUGH) Institutional Review Board
(Comité Ético de Investigación con Medicamentos del Hospital
General Universitario de Alicante, CEIM HGUA, reference
number 2019/003).
Each patient will be informed of the aims, methods, and
possible consequences (both potential beneﬁts and harms) of
the study. Participation in this study requires signed informed
consent. The patients will be able to withdraw from the study at
any time. Researchers will emphasize that refusing to be included
or withdrawing from the study will have no consequences on
their management or rights.
Data acquisition, management, and use will be in accordance
with the European Union regulation 2016/679, European
Parliament and Council, April 27, 2016. Each subject will be
assigned a code, and all data will be recorded using that number.
Only the attending physicians will know the relationship between
the code and patient’s identity. Access to personal information
will be restricted to the study physician and collaborators, health
authorities, and DSMB members, only if needed for safety issues,
to review study data and proceedings, but always maintaining
patients’ conﬁdentiality.
All data generated during this study are intended to be
published. The WATERFALL trial has been registered in
ClinicalTrials.gov (number pending).
General rules for authorship are explained in Table 2.
AUTHOR CONTRIBUTIONS
Ed-M was the trial sponsor and PI. The study was designed
by Ed-M, FB, and JB. PM reviewed the statistics. AV-R and
KC-J critically assessed the study design. All authors edited the
manuscript, and read and approved the ﬁnal manuscript.
FUNDING
This was a researcher driven study funded by the following
grants: Spanish Government: Proyectos de Investigación en
Salud, convocatoria 2019, Acción Estratégica en Salud 2017–
2020 (identiﬁer: PI19/01628) and Spanish Association of
Gastroenterology (AEG): Gonzalo Miño Grant for multicenter
trials 2019, AEG (identiﬁer: Beca AEG Gonzalo-Miño 2019).
ACKNOWLEDGMENTS
This study was endorsed by the Spanish Association of
Gastroenterology
(AEG)
and
the
Spanish
Association
of
Pancreatology (AESPANC).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online
at:
https://www.frontiersin.org/articles/10.3389/fmed.
2020.00440/full#supplementary-material
REFERENCES
1. Peery AF, Crockett SD, Murphy CC, Lund JL, Dellon ES, Williams JL,
et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases
in the United States: update 2018. Gastroenterology. (2018) 156:254–
72.e11. doi: 10.1053/j.gastro.2018.08.063
2. Sternby H, Bolado F, Canaval-Zuleta HJ, Marra-Lopez C, Hernando-Alonso
AI, Del-Val-Antonana A, et al. Determinants of severity in acute pancreatitis: a
nation-wide multicenter prospective cohort study. Ann Surg. (2019) 270:348–
55. doi: 10.1097/SLA.0000000000002766
3. Garcia-Rayado G, Cardenas-Jaen K, de-Madaria E. Towards evidence-based
and personalised care of acute pancreatitis. United Eur Gastroenterol J. (2020)
8:403–9. doi: 10.1177/2050640620903225
4. Tenner
S,
Baillie
J,
DeWitt
J,
Vege
SS,
American
College
of
Gastroenterology.
American
College
of
Gastroenterology
guideline:
management of acute pancreatitis. Am J Gastroenterol. (2013) 108:1400–15;
16. doi: 10.1038/ajg.2013.218
5. Baillargeon
JD,
Orav
J,
Ramagopal
V,
Tenner
SM,
Banks
PA.
Hemoconcentration as an early risk factor for necrotizing pancreatitis.
Am J Gastroenterol. (1998) 93:2130–4. doi: 10.1111/j.1572-0241.1998.00608.x
6. de-Madaria
E,
Garg
PK.
Fluid
therapy
in
acute
pancreatitis–
aggressive
or
adequate?
Time
for
reappraisal.
Pancreatology.
(2014)
14:433–5. doi: 10.1016/j.pan.2014.09.008
7. de-Madaria E, Soler-Sala G, Sanchez-Paya J, Lopez-Font I, Martinez J,
Gomez-Escolar L, et al. Inﬂuence of ﬂuid therapy on the prognosis of acute
pancreatitis: a prospective cohort study. Am J Gastroenterol. (2011) 106:1843–
50. doi: 10.1038/ajg.2011.236
8. Singh VK, Gardner TB, Papachristou GI, Rey-Riveiro M, Faghih M,
Koutroumpakis E, et al. An international multicenter study of early
intravenous ﬂuid administration and outcome in acute pancreatitis.
United Eur Gastroenterol J. (2017) 5:491–8. doi: 10.1177/20506406166
71077
9. Mao EQ, Tang YQ, Fei J, Qin S, Wu J, Li L, et al. Fluid therapy for severe acute
pancreatitis in acute response stage. Chin Med J (Engl). (2009) 122:169–73.
doi: 10.3760/cma.j.issn.0366-6999.2009.02.011
10. Mao EQ, Fei J, Peng YB, Huang J, Tang YQ, Zhang SD. Rapid
hemodilution
is
associated
with
increased
sepsis
and
mortality
among
patients
with
severe
acute
pancreatitis.
Chin
Med
J
(Engl).
(2010)
123:1639–44.
doi:
10.3760/cma.j.issn.0366-6999.2010.
13.005
Frontiers in Medicine | www.frontiersin.org
8
September 2020 | Volume 7 | Article 440

Bolado et al.
Fluid Resuscitation in Acute Pancreatitis
11. Buxbaum JL, Quezada M, Da B, Jani N, Lane C, Mwengela D, et al. Early
aggressive hydration hastens clinical improvement in mild acute pancreatitis.
Am J Gastroenterol. (2017) 112:797–803. doi: 10.1038/ajg.2017.40
12. de-Madaria E, Martinez JF, Aparicio JR, Lluis F. Aggressive ﬂuid resuscitation
in acute pancreatitis: in aqua sanitas? Am J Gastroenterol. (2017) 112:1617–
8. doi: 10.1038/ajg.2017.222
13. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG,
et al. Classiﬁcation of acute pancreatitis−2012: revision of the Atlanta
classiﬁcation and deﬁnitions by international consensus. Gut. (2013) 62:102–
11. doi: 10.1136/gutjnl-2012-302779
14. de-Madaria E, Sanchez-Marin C, Carrillo I, Vege SS, Chooklin S,
Bilyak A, et al. Design and validation of a patient-reported outcome
measure scale in acute pancreatitis: the PAN-PROMISE study. Gut.
(2020). doi: 10.1136/gutjnl-2020-320729. [Epub ahead of print].
15. Chan AW, TetzlaﬀJM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al.
SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical
trials. BMJ. (2013) 346:e7586. doi: 10.1136/bmj.e7586
16. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research
electronic data capture (REDCap)–a metadata-driven methodology and
workﬂow process for providing translational research informatics support. J
Biomed Inform. (2009) 42:377–81. doi: 10.1016/j.jbi.2008.08.010
17. Sharma A, Bhatt DL, Calvo G, Brown NJ, Zannad F, Mentz RJ. Heart failure
event deﬁnitions in drug trials in patients with type 2 diabetes. Lancet Diabetes
Endocrinol. (2016) 4:294–6. doi: 10.1016/S2213-8587(16)00049-8
18. Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial
medical treatment of acute pancreatitis: American Gastroenterological
Association Institute technical review. Gastroenterology. (2018) 154:1103–
39. doi: 10.1053/j.gastro.2018.01.031
19. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement:
updated guidelines for reporting parallel group randomised trials. BMJ. (2010)
340:c332. doi: 10.1136/bmj.c332
20. de Madaria E, Martinez J, Lozano B, Sempere L, Benlloch S, Such J, et al.
Detection and identiﬁcation of bacterial DNA in serum from patients with
acute pancreatitis. Gut. (2005) 54:1293–7. doi: 10.1136/gut.2004.047514
21. de-Madaria E, Herrera-Marante I, Gonzalez-Camacho V, Bonjoch L,
Quesada-Vazquez N, Almenta-Saavedra I, et al. Fluid resuscitation with
lactated Ringer’s solution vs normal saline in acute pancreatitis: a triple-
blind, randomized, controlled trial. United Eur Gastroenterol J. (2018) 6:63–
72. doi: 10.1177/2050640617707864
22. Acevedo-Piedra NG, Moya-Hoyo N, Rey-Riveiro M, Gil S, Sempere
L, Martinez J, et al. Validation of the determinant-based classiﬁcation
and revision of the Atlanta classiﬁcation systems for acute pancreatitis.
Clin
Gastroenterol
Hepatol.
(2014)
12:311–6. doi:
10.1016/j.cgh.2013.
07.042
Conﬂict of Interest: The authors declare that the research was conducted in the
absence of any commercial or ﬁnancial relationships that could be construed as a
potential conﬂict of interest.
Copyright
©
2020
Bolado,
Buxbaum,
Vaillo-Rocamora,
Cárdenas-Jaén,
Maisonneuve and de-Madaria. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
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September 2020 | Volume 7 | Article 440