ORIGINAL ARTICLE

Large Volume Fluid Resuscitation for Severe Acute

Pancreatitis is Associated With Reduced Mortality
A Multicenter Retrospective Study
Takahiro Yamashita, MD,*† Masayasu Horibe, MD,‡§
Masamitsu Sanui, MD, PhD,∥ Mitsuhito Sasaki, MD,¶
Hirotaka Sawano, MD, PhD,# Takashi Goto, MD,**
Tsukasa Ikeura, MD, PhD,†† Tsuyoshi Hamada, MD, PhD,‡‡
Takuya Oda, MD,§§ Hideto Yasuda, MD,∥∥ Yuki Ogura, MD, PhD,§
Dai Miyazaki, MD,¶¶ Kaoru Hirose, MD,## Katsuya Kitamura, MD, PhD,***
Nobutaka Chiba, MD, PhD,††† Tetsu Ozaki, MD,‡‡‡
Toshitaka Koinuma, MD,§§§ Taku Oshima, MD, PhD,∥∥∥
Tomonori Yamamoto, MD, PhD,¶¶¶ Morihisa Hirota, MD, PhD,###
Yukiko Masuda, MD,**** Natsuko Tokuhira, MD,††††
Mioko Kobayashi, MD,‡‡‡‡ Shinjiro Saito, MD,§§§§ Junko Izai, MD,∥∥∥∥
Alan K. Lefor, MD, MPH, PhD,¶¶¶¶ Eisuke Iwasaki, MD, PhD,‡
Takanori Kanai, MD, PhD,‡ and Toshihiko Mayumi, MD, PhD####

Methods: We conducted a multicenter retrospective study at 44

Background and Aims: Although fluid resuscitation is critical in acute
pancreatitis, the optimal fluid volume is unknown. The aim of this
study is to evaluate the association between the volume of fluid
administered and clinical outcomes in patients with severe acute
pancreatitis (SAP).
institutions in Japan. Inclusion criteria were age 18 years or older,
and diagnosed with SAP from 2009 to 2013. Patients were stratified
into 2 groups: administered fluid volume <6000 and ≥ 6000 mL in
the first 24 hours. We evaluated the association between the 2
groups and clinical outcomes using multivariable logistic regression

Received for publication December 9, 2017; accepted March 15, 2018.

From the *Emergency Medical Center, Fukuyama City Hospital, Zao-cho, Fukuyama City; **Department of Anesthesiology and Intensive Care,
Hiroshima City Hiroshima Citizens Hospital, Motomachi, Naka-ku, Hiroshima City, Hiroshima; †Acute Care Medical Center, Hyogo Prefectural
Kakogawa Medical Center, Kanno-cho, Kakogawa City, Hyogo; ‡Division of Gastroenterology and Hepatology, Department of Internal
Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku; §Department of Gastroenterology and Hepatology, Tokyo Metro-
politan Tama Medical Center, Musashidai, Fuchu City; ¶Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center
Hospital, Tsukiji, Chuo-ku; ‡‡Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku;
∥∥Department of Emergency and Critical Care Medicine, Japanese Red Cross Musashino Hospital, Kyounancho, Musashino City; ***Division of
Gastroentelology, Department of Medicine, Showa University School of Medicine, Hatanodai, Shinagawa-ku; †††Department of Emergency and
Critical Care Medicine, Nihon University Hospital, Kanda-Surugadai, Chiyoda-ku; ‡‡‡‡Tertiary Emergency Medical Center, Tokyo Metro-
politan Bokutoh Hospital, Kotobashi, Sumida-ku; §§§§Intensive Care Unit, Department of Anesthesiology, Jikei University School of Medicine,
Nishi-Shinbashi, Minato-ku, Tokyo; ∥Department of Anesthesiology and Critical Care Medicine, Jichi Medical University Saitama Medical
Center, Amanumacho, Omiya-ku, Saitama; #Senri Critical Care Medical Center, Osaka Saiseikai Senri Hospital, Tsukumodai, Suita; ††The
Third Department of Internal Medicine, Kansai Medical University, Shinmachi, Hirakata; ¶¶¶Department of Traumatology and Critical Care
Medicine, Osaka City University, Asahimachi, Abenoku, Osaka City, Osaka; §§Department of General Internal Medicine, Iizuka Hospital,
Yoshiomachi, Iizuka-shi; ####Department of Emergency Medicine, School of Medicine, University of Occupational and Environmental Health,
Iseigaoka, Yahata Nishi, KitaKyushu, Fukuoka; ¶¶Advanced Emergency Medical and Critical Care Center, Japanese Red Cross Maebashi
Hospital, Asahi-cho, Maebashi City, Gunma; ##Department of Emergency Medicine, Shonan Kamakura General Hospital, Okamoto, Kama-
kura City, Kanagawa; ‡‡‡Department of Acute care and General Medicine, Saiseikai Kumamoto Hospital, Chikami, minami-ku, Kumamoto
city, Kumamoto; §§§Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of
Medicine; ¶¶¶¶Department of Surgery, Jichi Medical University, Yakushiji, Shimotsuke, Tochigi; ∥∥∥Department of Emergency and Critical Care
Medicine, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba City, Chiba; ###Division of Gastroenterology, Tohoku
University Hospital, Seiryo-cho, Aoba-ku; ∥∥∥∥Department of Surgery, Saka General Hospital, Nishiki-cho, Shiogama City, Miyagi;
****Emergency and Critical Care Center, National Hospital Organization Nagasaki Medical Center, Kubara, Omura, Nagasaki; and
††††Division of Intensive Care Medicine, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
T.Yamashita, M.Horibe, M.Sanui, and M.Sasaki: literature search. M.Horibe, M.Sanui, M.Sasaki, and T.M.: study concept and design. T.Yama-
shita, M.Horibe, M.Sanui, M.Sasaki, H.S., T.G., T.I., T.H., T.Oda, H.Y., Y.O., D.M., K.H., K.K., N.C., T.Ozaki, T.Koinuma, T.Oshima,
T.Yamamoto, M.Hirota, Y.M., N.T., M.K., S.S., J.I., E.I., T.Kanai, and T.M.: acquisition of data. T.Yamashita, M.Horibe, and M.Sanui:
analysis and interpretation of data. T.Yamashita, M.Horibe, M.Sanui, E.I., M.Hirota, T.Oshima, and A.K.L.: drafting of the manuscript.
T.Yamashita and M.Horibe: drafting tables and figures. T.Yamashita, M.Horibe, M.Sanui, M.Sasaki, H.S., T.G., T.I., T.H., T.Oda, H.Y., Y.O.,
D.M., K.H., K.K., N.C., T.Ozaki, T.Koinuma, T.Oshima, T.Yamamoto, M.Hirota, Y.M., N.T., M.K., S.S., J.I., A.K.L., E.I., T.Kanai, and
T.M.: critical revision of the manuscript for important intellectual content.
The authors declare that they have nothing to disclose.
Address correspondence to: Masamitsu Sanui, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Division of Critical Care
Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanumachou, Omiya-ku, Saitama, Saitama 330-8503, Japan
(e-mail: msanui@mac.com).
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCG.0000000000001046

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Yamashita et al
analysis. The primary outcome was in-hospital mortality. Secon-
dary outcomes included the incidence of pancreatic infection and
the need for surgical intervention.
Results: We analyzed 1097 patients, and the mean fluid volume
administered was 5618 ± 3018 mL (mean ± SD), with 708 and 389
patients stratified into the fluid <6000 mL and fluid ≥ 6000 mL
groups, respectively. Overall in-hospital mortality was 12.3%. The
fluid ≥ 6000 mL group had significantly higher mortality than the
fluid <6000 mL group (univariable analysis, 15.9% vs. 10.3%;
P < 0.05). In multivariable logistic regression analysis, admin-
istration of ≥ 6000 mL of fluid within the first 24 hours was sig-
nificantly associated with reduced mortality (odds ratio, 0.58;
P < 0.05). No significant association was found between the
administered fluid volume and pancreatic infection, or between the
volume administered and the need for surgical intervention.
Conclusions: In patients with SAP, administration of a large fluid
volume within the first 24 hours is associated with decreased
mortality.
Key Words: severe acute pancreatitis, fluid resuscitation, mortality,
pancreatic infection, surgical intervention
(J Clin Gastroenterol 2018;00:000–000)
T he severity of acute pancreatitis varies widely, from a mild
self-limited disease to one with a severe clinical course
complicated by multiple organ-system failure.1 In Japan, the
overall mortality of patients with acute pancreatitis is 2.6% but
increases to 10.1% when limited to patients with severe acute
pancreatitis (SAP).2 Multiple organ-system failure is the main
cause of death of patients in the early phase of SAP,3,4 whereas
infected pancreatic necrosis worsens the prognosis in patients
with late phase SAP.4,5
No pharmacologic therapy has been shown to improve
the prognosis of patients with SAP, while the quality of sup-
portive care including early fluid resuscitation is critically
important.1,6 Fluid resuscitation is a critical part of supportive
care, which maintains adequate intravascular volume by
compensating for fluid shifts to the third space.7 In fact, it is
recommended that initial fluid resuscitation should be at least
250 to 300 mL/h.8 Major clinical practice guidelines for acute
pancreatitis recommend the administration of adequate
intravenous fluids in the early stage of acute pancreatitis.9–12
However, a conflicting study showed that aggressive
fluid resuscitation may be associated with increased mor-
tality and morbidity in patients with SAP.13 There is a lack
of consensus regarding the details of optimal fluid admin-
istration such as the type of fluid, infusion rate and volume
of administration, and the physiological goals of fluid
resuscitation.6,14
The aim of this study is to evaluate the association
between the total volume of fluid resuscitation in the early
stage (first 24 h) and clinical outcomes in patients with SAP.
METHODS
Study Design and Patients
We conducted a secondary analysis of data from a
multicenter retrospective study of patients with SAP in
Japan, which was registered with the University Hospital
Medical Information Network Clinical Trials Registry
(registry number 000012220) and approved by the Institu-
tional Review Board or the Medical Ethics Committee
at each institution.15 The study was performed at 44
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J Clin Gastroenterol  Volume 00, Number 00, ’’ 2018
institutions in Japan, including 25 tertiary academic medical
centers, and community hospitals with intensive care units.
Inclusion criteria were age 18 years or older, and the diag-
nosis of SAP, from January 1, 2009 to December 31, 2013.
Acute pancreatitis was diagnosed if the patient presented
with at least 2 of the following 3 features: (1) acute pain and
tenderness in the upper abdomen; (2) elevated pancreatic
enzyme levels in the blood and urine; or (3) findings of acute
pancreatitis as detected by ultrasonography, computed
tomography (CT) scan, or magnetic resonance imaging. The
diagnosis of SAP was based on criteria of the Japanese
Ministry of Health, Labour and Welfare (Japanese Severity
Score)10 (Table 1). We report the present study in accord-
ance with the Strengthening Reporting of Observational
studies in Epidemiology guidelines.16
Data Collection
Data were collected retrospectively, including patient
age, gender, etiology of acute pancreatitis, acute physiology
and chronic health evaluation (APACHE) II score, CT
severity index (CTSI), prognostic factors, and CT grade of
the Japanese Severity Score,10 Charlson index and severity
TABLE 1. Japanese Severity Score10
The Severity Scoring System of Acute Pancreatitis of the
Japanese Ministry of Health, Labour and Welfare (2008)
Prognostic factors (1 point for each factor)
1. Base excess ≤ −3 mEq/L or shock (systolic blood pressure
<80 mm Hg)
2. PaO2 ≤ 60 mm Hg (room air) or respiratory failure (ventilator
management is needed)
3. BUN ≥ 40 mg/dL (or Cr ≥ 2.0 mg/dL) or oliguria (daily urine
output <400 mL even after IV fluid resuscitation)
4. LDH ≥ 2 times of upper limit of normal
5. Platelet count ≤ 100,000/mm3
6. Serum Ca ≤ 7.5 mg/dL
7. CRP ≥ 15 mg/dL
8. No. positive measures in SIRS criteria ≥ 3
9. Age ≥ 70 y
CT grade by contrast-enhanced CT scan
1. Extrapancreatic progression of inflammation
Anterior pararenal space 0 point
Root of mesocolon 1 point
Beyond lower pole of kidney 2 points
2. Hypoenhanced lesion of the pancreas
The pancreas is conveniently divided into 3 segments
(head, body, and tail).
Localized in each segment or only 0 point
surrounding the pancreas
Covers 2 segments 1 point
Occupies entire ≥ 2 segments 2 points
1+2 = total scores
Total score = 0 or 1 Grade 1
Total score = 2 Grade 2
Total score ≥ 3 Grade 3
Assessment severity: (1) if prognostic factors are scored as ≥ 3 points, or
(2) If CT grade is judged as grade ≥ 2, the severity grading is evaluated to be
as “severe.”
Measures in SIRS diagnostic criteria: (1) temperature > 38°C or <36°C;
(2) heart rate > 90 beats/min; (3) ventilatory rate > 20 breaths/min or PaCO2
<32 torr; (4) WBC > 12,000 cells/mm3, <4000 cells/mm3, or > 10% immature
(band) forms.
BUN indicates blood urea nitrogen; CRP, C-reactive protein; CT,
computed tomography; IV, intravenous; LDH, lactate dehydrogenase; PaO2,
partial pressure of oxygen in blood; SIRS, systemic inflammatory response
syndrome; WBC, white blood cell.
J Clin Gastroenterol  Volume 00, Number 00, ’’ 2018
grade of the revised Atlanta classification.17 Acute pan-
creatitis was classified into 4 categories according to the
etiology (alcohol, gallstones, idiopathic, and others).18
Treatments analyzed included administered fluid vol-
ume within the first 24 hours after diagnosis, administration
of enteral nutrition within the first 48 hours after diagnosis,
administration of prophylactic antibiotics, continuous
regional arterial infusion (CRAI) of protease inhibitors,
mechanical ventilation, and renal replacement therapy.
Fluids were defined only as intravenously infused fluids.
Oral intake, enteral nutrition, and other nonintravenous
fluid intakes were excluded from analysis.
Outcomes
The primary outcome was in-hospital mortality. Sec-
ondary outcomes included the incidence of pancreatic
infection and the need for surgical intervention. We defined
pancreatic infection as the presence of bacteria in a blood
culture or local culture obtained by percutaneous, image-
guided, or endoscopic fine-needle aspiration, or the presence
of extraluminal gas in the pancreatic and/or peripancreatic
tissues on contrast-enhanced CT scan. Surgical interventions
included percutaneous, endoscopic, laparoscopic, or lapa-
rotomy drainage or necrosectomy for infected acute necrotic
collections or walled-off necrosis, interventional radiologic,
or endoscopic treatment for bleeding, etc.
Statistical Analysis
On the basis of the recommendation that initial fluid
administration should be at least 250 mL/h,8 we divided the
cohort into 2 groups according to the fluid volume admin-
istered within the first 24 hours: <6000 and ≥ 6000 mL.
Differences between the 2 groups were analyzed by the
Student t test or the Wilcoxon rank-sum tests for continuous
variables and the χ2 tests for categorical variables.
Multivariable logistic regression analysis was used to
evaluate the independent effect of fluid volume on clinical
outcomes in patients with SAP. In multivariable analysis,
FIGURE 1. Study flow. CT indicates computed tomography.
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Effect of Fluid Therapy in Severe Acute Pancreatitis
covariables included age, gender, etiology, APACHE II
score, Charlson index, CTSI, prognostic factors of the
Japanese Severity Score,10 enteral nutrition within first
48 hours, CRAI of protease inhibitors, administration of
prophylactic antibiotics, mechanical ventilation, and renal
replacement therapy. As a sensitivity analysis, we conducted
an identical analysis for the subgroup of patients with SAP
diagnosed according to the revised Atlanta classification.17
We performed another subgroup analysis for patients
who required open surgery, a percutaneous approach or an
endoscopic approach. We additionally evaluated the
association between fluid resuscitation and mortality in
multivariable analysis for each of the 3 interventions (open
surgery, percutaneous approach, and endoscopic approach).
Each factor was included in multivariable analysis. A
2-sided P < 0.05 was considered statistically significant. All
statistical analysis was performed with JMP (r) statistical
software version 11.2 (SAS Institute Inc., Cary, NC).
RESULTS
Patient Characteristics
A total of 1159 patients with SAP were enrolled. In total,
41 patients who did not undergo contrast-enhanced CT scan
and 21 patients who had at least 1 missing data point for
variables used in the multivariable analysis were excluded,
leaving 1097 patients for analysis (Fig. 1). The mean volume of
fluid administered was 5618 ± 3038 mL (mean ± SD) within
the first 24 hours (Fig. 2). In total, 708 patients were classified
into the fluid <6000 mL group, and 389 patients into the fluid
≥ 6000 mL group (Fig. 1). Table 2 shows the clinical charac-
teristics of the study patients. The fluid ≥ 6000 mL group was
significantly younger and had a higher proportion of males
than the fluid <6000 mL group. There were significant differ-
ences between the 2 groups with regard to the etiology of SAP.
The fluid ≥ 6000 mL group had a significantly higher severity
as showed by the APACHE II scores (P < 0.001), prognostic
factors of the Japanese Severity Score10 (P < 0.001), CTSI
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Yamashita et al J Clin Gastroenterol  Volume 00, Number 00, ’’ 2018

FIGURE 2. Administered fluid volume within the first 24 hours. The mean fluid volume administered within the first 24 hours to all
patients was 5618 ± 3038 mL (mean ± SD).

(P < 0.001), and proportion of SAP according to the revised

TABLE 2. Clinical Characteristics of Patients and Treatments Atlanta classification17 (P < 0.001) compared with the fluid
Fluid Fluid <6000 mL group.
<6000 mL ≥ 6000 mL
(n = 708) (n = 389) P
Treatment
Age [mean (SD)] (y) 60.4 (17.8) 55.5 (16.5) < 0.001 The mean administered fluid volume in the fluid
Men [N (%)] 450 (63.6) 290 (74.6) < 0.001 ≥ 6000 mL group and the fluid <6000 mL group were
Etiology [N (%)] < 0.001
8706 ± 3011 and 3922 ± 1097 mL, respectively (P < 0.001)
Alcohol 243 (34.3) 193 (44.3)
Gallstone 150 (21.2) 54 (13.9) (Table 2). Early enteral nutrition and CRAI of protease
Idiopathic 170 (24.1) 60 (15.4) inhibitors were more frequently administered in the fluid
Other causes 145 (20.5) 82 (21.1) ≥ 6000 mL group (P < 0.001, <0.001, respectively). There
APACHE II score [mean 11.6 (6.94) 15.1 (8.20) < 0.001 was no significant difference in the rate of administration of
(SD)] prophylactic antibiotics (P = 0.08). Mechanical ventilation
Prognostic factors [mean 2.48 (2.03) 4.05 (2.29) < 0.001 and renal replacement therapy were more frequently
(SD)] required in the fluid ≥ 6000 mL group (P < 0.001).
CTSI [median (IQR)] 4 (4-6) 4 (4-8) < 0.001
Charlson index [median 0 (0-1) 0 (0-1) 0.20
(IQR)] Outcomes
Revised Atlanta < 0.001 The overall in-hospital mortality was 12.3%. On the basis
classification17 [N (%)]
Mild acute pancreatitis 254 (35.9) 58 (14.9)
of univariable analysis, in-hospital mortality in the ≥ 6000 mL
Moderately severe acute 287 (40.5) 130 (33.4) of fluid group was significantly higher than in the <6000 mL of
pancreatitis fluid group (P < 0.05) (Table 3). The incidence of pancreatic
Severe acute 167 (23.6) 201 (51.7) infection (P < 0.001) and the need for surgical intervention
pancreatitis (P < 0.001) in the fluid ≥ 6000 mL group were also sig-
Treatment [N (%)] nificantly more frequent than in the fluid <6000 mL group.
Fluid administered in 3922 (1097) 8706 (3011) < 0.001
the first 24 h [mean
(SD)] (mL)
Enteral nutrition within 167 (23.6) 132 (33.9) < 0.001 TABLE 3. Outcomes of the 2 Study Groups
first 48 h N (%)
Prophylactic antibiotics 537 (75.9) 313 (80.5) 0.08
CRAI of protease 177 (25.0) 197 (50.6) < 0.001 Fluid <6000 mL Fluid ≥ 6000 mL
inhibitor (n = 708) (n = 389) P
Mechanical ventilation 129 (18.2) 201 (51.7) < 0.001
Renal replacement 75 (10.6) 87 (22.3) < 0.001 In-hospital 73 (10.3) 62 (15.9) < 0.05
therapy mortality
Pancreatic 69 (9.8) 67 (17.2) < 0.001
APACHE indicates acute physiology and chronic health evaluation; infection
CRAI, continuous regional arterial infusion; CTSI, Computed tomography Surgical 99 (14.0) 93 (23.9) < 0.001
severity index; IQR, interquartile range. intervention

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J Clin Gastroenterol  Volume 00, Number 00, ’’ 2018
TABLE 4. Association Between Administered Fluid ≥ 6000 mL
(n = 389) Versus Fluid <6000 mL (n = 708) and Clinical Outcomes
Unadjusted Adjusted*
OR 95% CI P OR 95% CI P
In-hospital 1.64 1.14-2.37 < 0.05 0.58 0.34-0.98 < 0.05
mortality
Pancreatic 1.93 1.34-2.77 < 0.001 0.76 0.48-1.19 0.23
infection
Surgical 1.93 1.41-2.65 < 0.001 0.95 0.63-1.42 0.81
intervention
*Multivariable logistic model includes variables: age, gender, etiology,
APACHE II score, Charlson index, computed tomography severity index,
prognostic factors of Japanese Severity Score,10 enteral nutrition within the
first 48 hours, continuous regional arterial infusion of protease inhibitors,
administration of prophylactic antibiotics, need for mechanical ventilation,
and renal replacement therapy.
APACHE indicates acute physiology and chronic health evaluation; CI,
confidence interval; OR, odds ratio.
On the basis of multivariable logistic regression anal-
ysis, fluid ≥ 6000 mL given within the first 24 hours is
associated with significantly decreased mortality [odds ratio
(OR), 0.58; 95% confidence interval (CI), 0.34-0.98]
(Table 4). No significant association was found between
administered fluid volume and the incidence of pancreatic
infection or the need for surgical intervention.
We performed subgroup analyses for patients diag-
nosed with SAP based on the revised Atlanta
classification.17 In total, 167 patients were classified in the
fluid <6000 mL group, and 201 patients classified in the
fluid ≥ 6000 mL group. There were no significant differences
between the 2 groups with regard to in-hospital mortality
(fluid <6000 mL: 35.3% vs. fluid ≥ 6000 mL: 28.4%;
P = 0.15), the incidence of pancreatic infection (fluid
<6000 mL: 24.6% vs. fluid ≥ 6000 mL: 25.9%; P = 0.77) or
the need for surgical intervention (fluid <6000 mL: 32.3% vs.
fluid ≥ 6000 mL: 33.8%; P = 0.76). Administered fluid
≥ 6000 mL within the first 24 hours was associated with
significantly lower mortality (OR, 0.56; 95% CI, 0.32-0.98)
after adjusting for confounding factors with multivariable
logistic regression analysis (Table 5). No significant associ-
ation was found between administered fluid volume and the
TABLE 5. Subgroup Analysis
Unadjusted Adjusted*
OR 95% CI P OR 95% CI P respiratory failure.23 Another retrospective study also
In-hospital 0.72 0.47-1.13 0.15 0.56 0.32-0.98 < 0.05
mortality
Pancreatic infection 1.07 0.67-1.73 0.77 0.74 0.42-1.29 0.29
Surgical 1.07 0.69-1.66 0.76 0.80 0.46-1.38 0.42
intervention
Association between administered fluid ≥ 6000 mL (n = 167) versus fluid
<6000 mL (n = 201) and clinical outcomes of severe acute pancreatitis based
on the revised Atlanta classification.17
*Multivariable logistic model includes variables: age, gender, etiology,
APACHE II score, Charlson index, Computed tomography severity index,
prognostic factors of the Japanese Severity Score,10 enteral nutrition within
the first 48 hours, continuous regional arterial infusion of protease inhibitors,
administration of prophylactic antibiotics, need for mechanical ventilation,
and renal replacement therapy.
APACHE indicates acute physiology and chronic health evaluation; CI,
confidence interval; OR, odds ratio.
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Effect of Fluid Therapy in Severe Acute Pancreatitis
incidence of pancreatic infection or the need for surgical
intervention.
As a subgroup analysis, we also performed a multi-
variable analysis including the 3 interventions (open surgery:
n = 52, percutaneous approach: n = 67, endoscopic approach:
n = 51). There were 170 patients who underwent these treat-
ments, including 59 patients (34.7%) who died. In the multi-
variable analysis, administered fluid ≥ 6000 mL within the first
24 hours was not associated with lower mortality (OR, 0.86;
95% CI, 0.34-2.16). Each of these 3 interventions was not
associated with lower mortality (P = 0.68).
DISCUSSION
We undertook this study to evaluate the association
between the volume of fluid administered early in the course
of treating patients with SAP and clinical outcomes. Patients
who were given ≥ 6000 mL of fluid within the first 24 hours
had higher severity, morbidity, and mortality than those
who were given <6000 mL of fluid within the first 24 hours.
However, in multivariable analysis, administration of fluid
≥ 6000 mL within the first 24 hours was associated with
decreased mortality.
Early fluid resuscitation is critical for the treatment of
patients with acute pancreatitis.1,6 It is generally accepted
that intravascular fluid losses should be corrected in the
early stage of acute pancreatitis.6 In the early phase of
the disease, intravascular fluid shifts to the extravascular
space due to increased vascular permeability as a result of
the inflammatory response.7,19 This process causes hemo-
concentration and decreased perfusion pressure, which may
lead to pancreatic necrosis.19 The hematocrit on admission
≥ 47% or failure to decrease the hematocrit within the first
24 hours after admission is a risk factor for the development
of pancreatic necrosis.20 In addition, 2 retrospective studies
reported that early fluid resuscitation, defined as receiving
more than one third within the first 24 hours of presentation
of the total fluid volume administered in the first 72 hours,
was associated with reduced mortality21 and morbidity.22
These findings suggest that early fluid resuscitation, espe-
cially within the first 24 hours after the diagnosis of acute
pancreatitis, is crucial.
Although early fluid administration is generally
accepted as standard supportive care, conflicting data sug-
gest that early fluid resuscitation may cause complications.
A prospective study reported that administration of
> 4100 mL of fluid during the first 24 hours in patients with
acute pancreatitis was associated with a higher incidence of
reported that patients receiving ≥ 4000 mL during the first
24 hours of admission developed more respiratory
complications.24 To the best of our knowledge, however, no
previous single study has shown an association between the
administered fluid volume and mortality.23,24
We did not find statistically significant significances
between fluid volume administered during first 24 hours and
the incidence of pancreatic infection, or between the fluid
volume administered and the need for surgical intervention in
multivariable analysis. In a retrospective study, the persistence
of hemoconcentration at 24 hours after admission was asso-
ciated with pancreatic necrosis, but administered fluid volume
was not associated with pancreatic necrosis.25 A systematic
review reported no significant difference between aggressive
fluid resuscitation and pancreatic necrosis and operative
intervention.14 These findings may indicate that complications,
www.jcge.com |5
Yamashita et al
such as pancreatic infection or necrosis, were not affected by
the fluid volume administered but rather were affected by the
severity of the disease itself. There is no significant association
between administered fluid volume and mortality in subgroup
analysis for patients who required open surgery, percutaneous
approach, or endoscopic approach. Neither fluid volume nor
any of the 3 interventions have a significant association with
mortality, possibly due to the small sample size with insuffi-
cient statistical power.
The volume of fluid administered in this study was
greater than in previous studies.21–24 The present study
includes only patients with SAP and a majority of study
institutions were considered to have followed the guidelines
recommendations. The American College of Gastro-
enterology guidelines recommend aggressive fluid resusci-
tation defined as 250 to 500 mL/h for all patients unless
cardiovascular or renal comorbidities exist9 and also state
that “early aggressive intravenous hydration is most bene-
ficial during the first 12 to 24 hours, and may have little
benefit beyond this time period.”9 Although these recom-
mendations do not define a daily target dose, the daily
amount by calculation (total 6000 to 12,000 mL/24 h) is
comparable to the fluid volume administered in this study.
The American Gastroenterological Association technical
review states that “in severe acute pancreatitis, fluid needs of
5 L or more daily are not uncommon.”11 The Japanese
guideline for the treatment of patients with acute pan-
creatitis also recommends rapid fluid resuscitation (150 to
600 mL/h) to treat shock and dehydration.10 Although the
fluid ≥ 6000 mL group had higher severity than the fluid
<6000 mL group, the fluid ≥ 6000 mL group had a lower
risk of mortality when adjusted for severity. Although the
universal cut-off value (eg, 6000 mL) for all patients cannot
be determined, there is a group of patients who require a
large volume infusion to improve outcomes. The results may
indicate that large volume resuscitation is a critical part of
the management of patients with severe pancreatitis.
Mao et al13 reported that aggressive fluid resuscitation
increased mortality and complications including respiratory
failure, abdominal compartment syndrome, and sepsis.
However, aggressive fluid resuscitation in the study by Mao
and colleagues represented the rate of fluid administration
rather the total volume in the early stage. The fluid infusion
rate in the aggressive group was 10 to 15 mL/kg/h and in
the control group was 5 to 10 mL/kg/h.13 The total mean
volume of fluid from admission to the first day was similar
comparing the aggressively resuscitated group (9535 mL:
crystalloids 6855 mL, colloids 2680 mL) and the control
group (8387 mL: crystalloids 5841 mL, colloids 2546 mL).13
Thus, the comparison in the Mao et al study13 (rate) was
different from that in the present study (total volume). As
the data in the present study are limited only to the volume
of fluid, we could not define an optimal rate of fluid
infusion.
This study has several acknowledged limitations. This
is a multicenter retrospective study in which protocols for
fluid resuscitation were not consistent among participating
institutions. However, all participating institutions are
believed to have followed the Japanese guidelines for the
management of patients with acute pancreatitis suggesting
early fluid administration,10 and had sufficient experience in
treating patients with SAP. Second, the retrospective nature
of the study precludes adjustments for undefined con-
founders. Because of the large study population, we
were able to adjust for other confounding factors by
6 | www.jcge.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.
J Clin Gastroenterol  Volume 00, Number 00, ’’ 2018
multivariable analysis. Third, we included patients with
SAP diagnosed by the Japanese Severity Score,10 severity
assessment criteria that have been validated only in Japa-
nese patients. Therefore, we performed subgroup analysis
for patients with SAP based on the revised Atlanta
classification17 and found consistent associations between
total volume of fluid administered and outcomes. Fourth,
the type of fluids administered were unknown in our cohort.
The Japanese guideline recommends balanced electrolyte
solutions, such as lactated Ringer’s solution, for fluid
resuscitation.10 Further studies will be needed to identify the
optimal fluid for administration to patients with SAP.
Finally, the volume of fluid resuscitation given after the first
24 hours following admission was unclear, and may affect
the outcomes.
In conclusion, the administration of a large volume of
fluid within the first 24 hours of the onset of SAP is asso-
ciated with lower mortality. Large volume fluid resuscita-
tion may be associated with an improved prognosis in
patients with SAP.
ACKNOWLEDGMENTS
The authors acknowledge for Kazuichi Okazaki,
Tsuyoshi Takeda, Seiya Suzuki, Jun Kataoka, Tomohiro
Adachi, Wataru Shinomiya, Shin Namiki, Sakue Masuda,
Tomoaki Hashida, Naoki Shinyama, Hitoshi Yamamura,
Takashi Moriya, Kunihiro Shirai, Kazuo Inui, Satoshi
Yamamoto, Kyoji Oe, Takashi Muraki, Tetsuya Ito, Junichi
Sakagami, Hiroaki Yasuda, Yoshinori Azumi, Masayuki
Kamochi, Keiji Nagata, Nobuyuki Saito, Mizuki Sato, Kyohei
Miyamoto, Koji Saito, Kazunori Takeda, Motohiro Sekino,
Tomoki Furuya, Yoshimoto Seki, Tetsuya Mine, Youhei
Kawashima, Naoyuki Matsuda, Masato Inaba, Mineji Hay-
akawa, Takuyo Misumi and Yuki Takeda with the support of
the data collection at 44 institutions (Osaka Saiseikai Senri
Hospital, Hiroshima City Hiroshima Citizens Hospital,
Kansai Medical University Hirakata Hospital, The University
of Tokyo Hospital, Iizuka Hospital, Japanese Red Cross
Musashino Hospital, Tokyo Metropolitan Tama Medical
Center, Japanese Red Cross Maebashi Hospital, Shonan
Kamakura General Hospital, Showa University Hospital, Nihon
University Hospital, Saiseikai Kumamoto Hospital, Fukuyama
City Hospital, Jichi Medical University Hospital, Chiba Uni-
versity Hospital, Osaka City University Hospital, Tohoku
University Hospital, Nihon University Itabashi Hospital,
Gifu University Hospital, Second Teaching Hospital, Fujita
Health University, Asahi General Hospital, Shinshu University
Hospital, National Hospital Organization Nagasaki Medical
Center, University Hospital, Kyoto Prefectural University of
Medicine, Mie University Hospital, Hospital of the University of
Occupational and Environmental Health, Nippon Medical
School Chiba Hokusoh Hospital, Jichi Medical University,
Saitama Medical Center, Wakayama Medical University Hos-
pital, Tokyo Metropolitan Bokutoh Hospital, Jikei University
School of Medicine, Saka General Hospital, National Hospital
Organization Sendai Medical Center, Nagasaki University
Hospital, Keio University School of Medicine, Japanese Red
Cross Akita Hospital, Ibaraki Prefectural Central Hospital,
Tokai University Hospital, Nagoya University Hospital, Hok-
kaido University Hospital, National Cancer Center, Akita City
Hospital, Kobe University Hospital, Tokyo Rosai Hospital).
The authors thank the Japanese Society of Education for
Physicians and Trainees in Intensive Care, and the Japanese
Society of Intensive Care Medicine.
J Clin Gastroenterol  Volume 00, Number 00, ’’ 2018
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