Nonaggressive Versus Aggressive Intravenous Fluid Therapy in Acute Pancreatitis With More Than 24 Hours From Disease Onset: A Randomized Controlled Trial

Abstract

Objective:
This study aimed to compare a "nonaggressive" hydration versus an "aggressive" hydration using Hartmann's solution in patients with acute pancreatitis (AP) with more than 24 hours from disease onset.

Methods:
We included 88 patients with AP with more than 24 hours from disease onset, and were randomized into 2 groups. Group I (n = 45) received a nonaggressive hydration (Hartmann's solution at 1.5 mL kg h for the first 24 hours and 30 mL kg during the next 24 hours), and group II (n = 43) received an aggressive hydration (bolus of Hartmann's solution 20 mL kg, followed by an infusion of 3 mL kg h for the first 24 hours and then 30 mL kg for the next 24 hours).

Results:
The mean volume of fluid administered was greater in group II (P < 0.001). We did not find differences when comparing both groups in reference to persistent systemic inflammatory response syndrome (P = 0.528), pancreatic necrosis (P = 0.710), respiratory complications (P = 0.999), acute kidney injury (P = 0.714), or length of hospital stay (P = 0.892).

Conclusions:
Our study suggests that the clinical evolution of patients with AP with more than 24 hours from disease onset is similar using an aggressive or nonaggressive hydration.

Full text

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Nonaggressive Versus Aggressive Intravenous Fluid Therapy in
Acute Pancreatitis With More Than 24 Hours From
Disease Onset
A Randomized Controlled Trial
Jesús Eduardo Cuéllar-Monterrubio, MD, Roberto Monreal-Robles, MD, Emmanuel I. González-Moreno, MD,
Omar D. Borjas-Almaguer, MD, José Luis Herrera-Elizondo, MD, Diego García-Compean, MD,
Héctor J. Maldonado-Garza, MD, and José Alberto González-González, MD
Objective: This study aimed to compare a “nonaggressive”hydration versus
an “aggressive”hydration using Hartmann's solution in patients with acute
pancreatitis (AP) with more than 24 hours from disease onset.
Methods: We included 88 patients with AP withmore than 24 hours from
disease onset, and were randomized into 2 groups. Group I (n = 45) received
a nonaggressive hydration (Hartmann's solution at 1.5 mL kg
−1
h
−1
for the
first 24 hours and 30 mL kg during the next 24 hours), and group II
(n = 43) received an aggressive hydration (bolus of Hartmann's solution
20 mL kg, followed by an infusion of 3 mL kg
−1
h
−1
for the first 24 hours
andthen30mLkgforthenext24hours).
Results: The mean volume of fluid administered was greater in group II
(P< 0.001). We did not f ind differences when comparing both groups in ref-
erence to persistent systemic inflammatory response syndrome (P= 0.528),
pancreatic necrosis (P= 0.710), respiratory complications (P=0.999),
acute kidney injury (P= 0.714), or length of hospital stay (P= 0.892).
Conclusions: Our study suggests that the clinical evolution of patients
with AP with more than 24 hours from disease onset is similar using an ag-
gressive or nonaggressive hydration.
Key Words: acute pancreatitis, fluid therapy, aggressive, nonaggressive,
late evolution
(Pan c re a s 2020;49: 579–583)
Acute pancreatitis (AP) is a common cause of hospitalization
with 275,000 annual admissions with an increasing trend.
1–4
In up to 20% of cases, patients with AP present with a complicated
disease course, with a mortality reported at 5% to 25%.
5
Resuscitation with intravenous fluids is currently the treat-
ment of choice in the first 24 hours from pain onset (“the golden
hours”).
6
There are different approaches to hydration in AP. Al-
though the American College of Gastroenterology suggests an ag-
gressive intravenous hydration, defined as 250 to 500 mL/h, the
Working Group of the International Association of Pancreatology/
American Pancreatic Association Acute Pancreatitis Guidelines
recommend a goal-directed intravenous fluid therapy with 5 to
10 mL kg
−1
h
−1
.
7,8
These hydration strategies are based on animal
models and observational data from clinical studies.
9,10
However,
it has recently been reported that patients who receive a lower vol-
ume of hydration have a lower incidence of complications.
11,12
Despite this, an important factor in the prevention of complica-
tions in AP is the time when hydration management starts in re-
gard to the initiation of symptoms.
13
Buxbaum et al
14
recently published that early aggressive hydra-
tion with Ringer's lactate solution is superior to standard hydration in
patients with mild AP. In our hospital, a large proportion of patients
with AP seek medical attention 24 hours after the onset of their symp-
toms.
15
No prospective trials in this specific group of patients have
been published in relation to the intravenous resuscitation strategy. This
prompted us to design a randomized clinical trial to compare a “nonag-
gressive”hydration with an “aggressive”hydration using Hartmann's
solution in patients with AP with more than 24 hours from disease
onset. We evaluated the AP severity, persistent systemic inflam-
matory response syndrome (SIRS), and local complications.
MATERIALS AND METHODS
We conducted a controlled, randomized, comparative clinical
trial from May 2015 to October 2016.
Patients
We studied all consecutive patients admitted to the emer-
gency department with diagnosis of AP. We included all patients
older than 18 years with more than 24 hours from disease onset.
The diagnosis of AP was determined by fulfilling at least 2 of
the 3 following criteria: (a) characteristic abdominal pain, (b)se-
rum amylase and/or lipase greater than 3 times the upper limit of
normal, and (c) cross-sectional abdominal imaging demonstrating
changes consistent with AP.
16
We excluded all patients with less than 24 hours of AP clin-
ical onset; patients who needed vasopressors; patients with severe
comorbidities such as New York Heart Association class II or greater
heart failure, or stage 3 or greater chronic kidney disease; patients
with suspicion or active acute infection(s) (acute cholangitis and/or
acute cholecystitis); pregnant patients; patients with postendoscopic
retrograde cholangiography pancreatitis; patients who received treat-
ment in another medical unit before their admission to our hospital;
and patients under treatment with β-blockers. Patients who did
not complete their clinical evolution in our hospital were eliminated.
The AP diagnosis was performed in the first 3 hours of ad-
mission, a member of the study protocol was contacted, and a
signed informed consent form was obtained from all patients
before randomization.
The study was authorized by the ethics committee of our hos-
pital and was registered (No. GA 15-006). Consolidated Standards
of Reporting Trials (CONSORT) recommendations were followed.
From the Servicio de Gastroenterología, Hospital Universitario “Dr. José Eleuterio
González,”Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.
Received for publication April 15, 2019; accepted February 13, 2020.
Address correspondence to: José Alberto González-González, MD, Servicio de
Gastroenterología, Facultad de Medicinay Hospital Universitario “Dr. José
EleuterioGonzález,”Universidad Autónoma de Nuevo León,Av. Madero y
Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo León 64460,
México (e‐mail: jalbertogastro@gmail.com).
The authors received no funding in the preparation of this article.
The authors declare no conflict of interests.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MPA.0000000000001528
ORIGINAL ARTICLE
Pancreas •Volume 49, Number 4, April 2020 www.pancreasjournal.com 579
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Intervention
We decided to perform our study using Hartmann's solution,
which is almost similar to Ringer's lactate solution. Patients who
were included in the study were randomized 1:1 in a period not
greater than 2 hours after the diagnosis of AP using a computer-
generated randomization sequence (Randomizer; Geoffrey C.
Urbaniak and Scott Plous, Wesleyan University) to receive a treat-
ment with nonaggressive hydration (group I) or an aggressive hy-
dration (group II) for the next 48 hours.
17
The nonaggressive scheme consisted of intravenous hydration
of Hartmann's solution at a rate of 1.5 mL kg
−1
h
−1
for the first
24 hours and subsequently 30 mL kg per 24 hours. Group II re-
ceived an aggressive hydration consisting of a bolus of Hartmann's
solutionatarateof20mLkgfollowedbyaninfusionof3mLkg
−1
h
−1
for the first 24 hours, and then 30 mL kg for the next 24 hours.
The following parameters were monitored during the study:
hourly vital signs; diuresis in milliliters per hour every 8 hours;
the levels of blood urea nitrogen (BUN), hematocrit, and lactate;
and SIRS data on admission and at 24 and 48 hours. Systemic in-
flammatory response syndrome was defined by the presence of 2
or more criteria: (a) heart rate >90 beats/min, (b) core temperature
<36°C or >38°C, (c) white blood count <4000 or >12,000/mm
3
,
and/or (d) respirations >20 breaths/min or PCO
2
<32 mm Hg. Organ
failure was defined using the modified Marshall scoring system ≥2,
and the severity of AP was classified according to the revised
Atlanta classification criteria: (a)mild,(b) moderately severe, and
(c) severe.
16,18
The clinical follow-up was carried out by the gastro-
enterology fellows directly involved in the study. Clinical improve-
ment was defined as the absence of SIRS and/or organ failure at
48 hours. Contrast-enhanced computed tomography (CT) was
performed in patients with organ failure, persistent abdominal pain,
oral intolerance, and/or persistent SIRS to evaluate local complications.
Sample Calculation
Sample size was calculated using a 2-proportion difference
with a confidence level of 95% and a power of 80%. The calculation
was based on estimating a clinical improvement in the targeted group
of 33% greater than the aggressive hydration group, adjusting the
losses to 15%. An n of 38 patients per group was estimated.
Statistical Analysis
The statistical analysis was performed using SPSS 20.0 statisti-
cal software (IBM Corp, Armonk, NY). Normality distribution was
determined using the Kolmogorov-Smirnov test. For the description
of demographic variables, we used mean (standard deviation [SD]),
median with range, frequencies, and percentages. Comparison be-
tween groups was performed by using the Student ttest or the
Mann-Whitney Utest for continuous variables according to normal-
ity. Categorical variables were compared between groups using the
χ
2
test or Fisher exact test. A P< 0.05 was considered significant.
RESULTS
A total of 200 patients with AP were admitted during the study
period. We excluded 110 patients. Of the remaining 90 patients,
2 had persistent hypotension at admission and did not improve with
an extra bolus of Hartmann's solution of 20 mL kg; therefore, it was
necessary to use vasopressors. These patients were eliminated from
the study and were not included in the statistical analysis (Fig. 1).
FIGURE 1. Study flow diagram.
Cuéllar-Monterrubio et al Pancreas •Volume 49, Number 4, April 2020
580 www.pancreasjournal.com © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Finally, we included 88 patients with AP with more than 24 hours
from disease onset. After randomization, we had 45 patients in
group I (nonaggressive) and 43 in group II (aggressive). In both
groups, female sex predominated (64.7%) as well as biliary etiology
(79.5%). The baseline characteristics were similar in both groups
(Table 1), including SIRS at admission, BUN, and hematocrit level.
The volume of fluids administered was greater in the aggres-
sive hydration (group II; 8540 vs 5125 mL; P< 0.001) at 48 hours.
In the nonaggressive(group I), 3 patients required an extra dose of
Hartmann's solution of 20 mL kg to achieve the hemodynamic
goals. These patients were included and analyzed.
Table 2 shows the clinical evolution. After 48 hours, clinical
improvement was observed in 69 patients: 37 patients (82.2%) for
group I versus 32 patients (74.4%) for group II. Fifteen patients
were admitted with SIRS, which persisted for morethan 48 hours:
7 patients (15.6%) for group I versus 8 patients (18.6%) for group
II. Four patients developed SIRS during the first 48 hours of AP
onset, which persisted for more than 48 hours: 1 patient (2.2%)
for group I versus 3 patients (7.0%) for group II. These results
did not reach statistical significance (P= 0.501).
Contrast-enhanced CT was performed to evaluate local
complications in 24 patients: 9 (20%) for group I versus 15
(34.8%) for group II. The mean time to CT scan was day 7
after admission.
There were no differences in severe AP in fluid collections,
pancreatic necrosis, respiratory and renal complications, and length
of hospital stay. No deaths were recorded during the study period.
DISCUSSION
In our study, the clinical evolution using nonaggressive ver-
sus aggressive hydration in patients with AP of more than 24 hours
after the onset of pain was similar in relation to AP severity, per-
sistent SIRS, and local complications.
A hydration that we have considered aggressive has been rec-
ommended in several publications.
6,7,14
This recommendation
originates from observational and experimental studies.
10
However,
there is no specific recommendation in patients with AP who are
admitted later than 24 hours of disease onset. In the first few hours
of the evolution of AP, multiple proinflammatory cytokines and va-
soactive mediators participate, such as tumor necrosis factor α,bra-
dykinin, interleukin (IL)-1, IL-2, IL-6, platelet activating factor, and
endothelin-1 with a peak at 36 hours from pain onset causing organ
dysfunction.
19
This has been an important point to justify that ag-
gressive hydration could decrease the circulating concentration of
these inflammatory mediators and therefore complications. Re-
cently, Buxbaum et al
14
published a study in patients with AP
without SIRS or organ failure on admission in which they used
hydration with Hartmann's solution in a directed versus aggres-
sive manner. They observed a faster clinical improvement in the
aggressive group, but they did not mention the time of onset of
AP. On the other hand, previous studies have shown that hydration
with >4.1 L during the first 24 hours of admission increases the
risk of developing organ failure, AP collections, respiratory and
renal failure, and mortality.
12,20
A recent study by the Cleveland
Clinic regarding the clinical evolution of patients with 24 hours
of AP onset without organ failure on admission, using aggressive
hydration of 4.8 versus 2 L in the first 24 hours, did not demon-
strate a benefit in their clinical evolution.
21
In our study, we included patients with AP whom at admission
did not have severe or decompensated comorbidities such as renal,
pulmonary, or cardiac failure, and those with severe hypotension
that required the use of vasopressors. We did, however, include pa-
tients with SIRS and Marshall score 2 or greater at admission
(Table 1). Most of our patients are young women with a biliary eti-
ology; this may have an important impact on our results.
15
It is important to mention that our gastroenterology fellows
were on call and contacted by the emergency department staff
when patients with AP were diagnosed. All the patients included
in the study were randomized, and the treatment started within
the first 4 hours after admission.
The nonaggressive hydration group received a smaller vol-
ume of fluid than did the aggressive hydration group (5130 vs
8540 mL; P< 0.001). Despite this, it was necessary to administer
more volume to 3 patients in the nonaggressive group (bolus of
Hartmann's solution 20 mL kg); these patients, however, did not
have subsequent complications. The clinical improvement was
similar in the 2 groups, and there was no difference in the presence
of SIRS on admission or persistent SIRS, or in those who devel-
oped SIRS after hospital admission (Table 2). In the 18 patients
with a Marshall score of ≥2 at admission (group I vs group II:
10 vs 8 patients, respectively), the clinical evolution in regard to
persistent SIRS or organ failure was not statistically different in
AP severity using the Revised Atlanta Classification.
16
The presence
TABLE 1. Baseline Characteristics at Admission
Variable Directed (n = 45) Aggressive (n = 43) P
Age, mean (SD), y 38.60 (15.07) 36.69 (15.93) 0.563
Sex, female, n (%) 27 (60) 30 (69.77)
Biliary AP, n (%) 37 (82.2) 33 (76.7)
Laboratory parameters, mean (SD)
Amylase, U/L 1534.4 (1317.5) 1508 (1412.7) 0.931
Lactate, mmol/L 1.18 (0.82) 1.06 (0.81) 0.521
Creatinine, mg/dL 0.82 (0.55) 0.75 (0.25) 0.436
BUN, mg/dL 12.26 (6.47) 11.58 (5.92) 0.605
Hematocrit, % 44.4 (6.5) 44.5 (5.1) 0.853
SIRS on admission, n (%) 18 (40) 17 (39.53) 0.999
Marshall score on admission, n (%) 0.404
0 25 (55.56) 21 (48.8)
1 10 (22.22) 14 (32.6)
≥2 10 (22.22) 8 (18.6)
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of complications such as fluid collections, pancreatic necrosis, re-
spiratory complications, and acute kidney injury was similar in
both groups as well as the length of hospital stay (Table 2).
In relation to the type of solutions used, Wu et al
22
demon-
strated a lower incidence of SIRS and a lower level of C-reactive
protein in patients with AP treated with Ringer's lactate solution
in the first 24 hours of admission, suggesting that this solution im-
proves the homeostasis of the intracellular pH and electrolyte bal-
ance. In another randomized clinical trial, Ringer's lactate was
superior to saline solution in relation to the presence of SIRS in
the first 24 hours of evolution; however, there was no difference
in the improvement of SIRS at 48 hours, length of hospital stay,
local complications, a decrease in serum markers, or mortality.
23
A recent meta-analysis reports that the use of Ringer's lactate
is associated with a lower incidence of persistent SIRS but not
of mortality; therefore, controversy persists about which solution(s)
should be recommended.
24
Recently, de-Madaria et al
25
performed a triple-blinded ran-
domized clinical trial in which patients with AP received Ringer's
lactate or saline solution, and evaluated the clinical and in vitro ef-
fects of hydration. At 72 hours after resuscitation, the patients in the
saline group received greater volume than did the Ringer's lactate
group (6904 [range, 6400–8600] mL vs 5900 [range, 4930–7002]
mL, P= 0.045]. There were no differences found in SIRS at 24,
48, or 72 hours, or in pancreatic or peripancreatic necrosis, persis-
tent organic failure, length of hospital stay, severity, or mortality in
both groups; however, in vitro, it was observed that Ringer's lac-
tate inhibited the induction of the inflammatory phenotype in
macrophages and activation of nuclear factor κB, a phenomenon
that was not observed in the group that received saline solution.
Serum markers such as BUN elevated at admission or its in-
crease during hospitalization has been associated with higher mor-
tality.
26
In our study, we did not find a statistically significant
difference in BUN levels (Table 1). Although the volume admin-
istered to the group of patients with nonaggressive hydration
was lower (5130 mL) than that of the aggressive hydration group
(8540 mL), the patients who developed elevated BUN did not de-
velop renal complications.
There was no mortality in our study. This may be explained
because our patients were mostly young people with a biliary eti-
ology and we excluded patients with severe comorbidities that
may put them at risk of fluid overload. We also excluded patients
who had suspicion of active infection; despite the fact that the
goals of sepsis management are similar to those of AP, these pa-
tients require antibiotic therapy, early initiation of vasopressors,
and occasionally invasive procedures.
The strengths of our study are that the cohort characteristics
were precisely defined, and both studied groups were homogenous
and randomized within 4 hour of admission. It is one of the few pro-
spective clinical trials in which 2 types of hydration are compared
with different volumes in patients with AP with more than 24 hours
from disease onset.
The weaknesses of our study are that it is not blinded, it was
carried out in a single center, the contrast-enhanced CTwas indi-
cated by the doctor in charge of the patient, and most of our pa-
tients were young women without severe comorbidities. Another
point to consider is the criteria we used to exclude the patients with
more severe disease atadmission,and this point may limit the gen-
eralizability of our result, although both groups studied did not
demonstrate differences in their clinical evolution by type of
hydration. Better criteria to define the degree of activity of
the inflammatory process such as the criteria proposed by the
American or Japanese Pancreas Associations may be useful. The
validation of these will be an important tool in future studies.
27
In conclusion, our study suggests that the clinical evolution
of patients with AP with more than 24 hours from disease onset
is similar using an aggressive or nonaggressive hydration with
Hartman's solution.
ACKNOWLEDGMENTS
We thank Dr Hector Eloy Tamez-Perez, Dr Enrique Delgadillo-
Esteban, Dr Susanna Scharrer-Cabello, and Dr Sergio Lozano-
Rodriguez for their help in calculating the sample size and in
translating and editing the article.
TABLE 2. Clinical Evolution
Variable Nonaggressive (n = 45) Aggressive (n = 43) 95% CI P
Administered volume (48 h), mean (SD), mL 5130 (1287) 8540 (1830) <0.001
SIRS ≥7 d, n (%) 6 (13.3) 6 (13.9) 0.26–4.33 0.999
Modified Atlanta classif ication, n (%) N/A 0.654
Mild 23 (55.1) 19 (44.2)
Moderately severe 14 (31.1) 13 (30.2)
Severe 8 (17.8) 11 (25.6)
Complications, n (%)
Fluid collection* 6 (13.3) 6 (13.9) 0.26–4.33 0.999
Pancreatic necrosis* 3 (6.6) 4 (9.3) 0.23–10.38 0.710
Respiratory 6 (13.3) 5 (11.6) 0.19–3.69 0.999
AKI 5 (11.1) 3 (6.9) 0.160–2.468 0.714
Length of hospital stay, median (range), d 7 (4–9) 7 (8–11) 0.892
Clinical improvement, n (%)
†
37 (82.2) 32 (74.4) 0.501
Persistent SIRS, n (%)
†
7(15.6) 8(18.6)
DevelopedSIRS,n(%)
†
1 (2.2) 3 (7.0)
*Only patients who underwent contrast-enhanced CT scan (nonaggressive, 9 [20%]; aggressive, 15 [34.8%]).
†
Outcomes at 48 hours.
AKI indicates acute kidney injury; N/A, not applicable.
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Pancreas •Volume 49, Number 4, April 2020 Less Versus More Fluids in Acute Pancreatitis
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