Chinese Medical Journal 2009;122(2):169-173
Fluid therapy for severe acute pancreatitis in acute response stage

MAO En-qiang,  TANG Yao-qing,  FEI Jian,  QIN Shuai,  WU Jun,  LI Lei,  MIN Dong ,  ZHANG Sheng-dao

MAO En-qiang (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

TANG Yao-qing (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

FEI Jian (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

QIN Shuai (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

WU Jun (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

LI Lei (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

MIN Dong (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

ZHANG Sheng-dao (Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China)

Correspondence to:ZHANG Sheng-dao,Department of General Surgery, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China (Tel: 86-21-64370045 ext. 666067. Fax:86-21-64370045 ext. 666067. E-mail:Email: maoeq@yeah.net)
Keywords
pancreatitis, acute necrotizing; resuscitation; acute response stage
Abstract

Background Fluid therapy for severe acute pancreatitis (SAP) should not only resolve deficiency of blood volume, but also prevent fluid sequestration in acute response stage. Up to date, there has not a strategy for fluid therapy dedicated to SAP. So, this study was aimed to investigate the effects of fluid therapy treatment on prognosis of SAP.
Methods Seventy-six patients were admitted prospectively according to the criteria within 72 hours of SAP onset. They were randomly assigned to a rapid fluid expansion group (Group I, n=36) and a controlled fluid expansion group (Group II, n=40). Hemodynamic disorders were either quickly (fluid infusion rate was 10–15 ml∙kg-1∙h-1, Group I) or gradually improved (fluid infusion rate was 5–10 ml∙kg-1∙h-1, Group II) through controlling the rate of fluid infusion. Parameters of fluid expansion, blood lactate concentration were obtained when meeting the criteria for fluid expansion. And APACHE II scores were obtained serially for 72 hours. Rate of mechanical ventilation, incidence of abdominal compartment syndrome (ACS), sepsis, and survival rate were obtained.
Results The two groups had statistically different (P <0.05) time intervals to meet fluid expansion criteria (Group I, 13.5±6.6 hours; Group II, (24.0±5.4) hours). Blood lactate concentrations were both remarkably lower as compared to the level upon admission (P <0.05) and reached the normal level in both groups upon treatment. It was only at day 1 that hematocrit was significantly lower in Group I (35.6%±6.8%) than in Group II (38.5%±5.4%) (P<0.01). Amount of crystalloid and colloid in group I ((4028±1980)ml and (1336±816)ml) on admission day was more than those of group II ((2472±1871)ml and (970±633)ml). No significant difference was found in the total amount of fluids within four days of admission between the two groups (P>0.05). Total amount of fluid sequestration within 4 days was higher in Group I ((5378±2751)ml) than in Group II ((4215±1998)ml, P <0.05). APACHE II scores were higher in Group I on days 1, 2, and 3 (P <0.05). Rate of mechanical ventilation was higher in group I (94.4%) than in group II (65%, P <0.05). The incidences of abdominal compartment syndrome (ACS) and sepsis were significantly lower in Group II (P <0.05). Survival rate was remarkably lower in Group I (69.4%) than in Group II (90%, P <0.05).
Conclusions Controlled fluid resuscitation offers better prognosis in patients with severe volume deficit within 72 hours of SAP onset.

Fluid resuscitation is the most important management during the first 72 hours after onset of severe acute pancreatitis (SAP). However, low efficacy of the fluid therapy could lead to severe complications that would compromise survival rate.1,2 Therefore, the two goals of early phase fluid resuscitation are amelioration of hypoxia of tissue and prevention of complications. Similar to septic shock, circulatory abnormalities (such as high cardiac output/low vascular resistance, peripheral vasodilation, myocardial depression and clinical manifestations that increase heart rate, disrupt blood pressure and deplete vascular volume) in SAP lead to imbalance between systemic oxygen delivery and oxygen demand, resulting in oxygen debt3 and multiple organ dysfunction syndrome (MODS).4 The systemic inflammatory response syndrome caused by SAP could also progress to capillary leakage syndrome (CLS), leading to body fluid sequestration. Within 72 hours (Gold time) after SAP onset, organs could still compensate for the CLS caused volume depletion. Meanwhile, body fluid sequestration is initiated during the Gold time. Generally, a rapid and massive fluid expansion treatment is given to the patients clinically to shorten tissue ischemia. However, complications, such as acute respiratory distress and extravascular fluid sequestration, greatly compromised the procedure. Therefore, in this study, controlled fluid resuscitation therapy was examined and its efficacy in reducing complications and improving prognosis was compared with those of the rapid fluid expansion approach.

METHODS

Approval for investigation
This prospective, randomized clinical trial was approved by the ethics committee for human research. An agreement was obtained from each patient or their legal guardian.

Patient eligibility
Eligible patients meeting the Atlanta criteria of diagnosis for SAP5 were enrolled within 72 hours after onset of the disease from March 2001 through December 2007. Criteria for inclusion were the fulfillment of at least three of the followings: heart rate (HR) ≥120 beats/min, mean arterial pressure (MAP) ≥85 mm Hg or ≤60 mm Hg, blood lactate concentration (BLC) ≥4 mmol/L, urine output (UO) ≤0.5 ml∙kg-1∙h-1 and hematocrit (HCT) ≥44%. Criteria for exclusion included any of the followings: Less than 18 or more than 70 years of age, pregnancy, chronic heart disease, pacemaker installation, chronic renal failure and SAP with uncertain etiology. Seventy -six patients were enrolled in the study. Etiologies were hyperlipidemia (17 cases), gallstone (55) and alcoholism (4). Patients were randomly assigned to rapid fluid expansion group (Group I, n=36) and controlled fluid expansion group (Group II, n=40).

Treatment of SAP
The patients were treated in the department of a 12-bed surgical intensive care unit (SICU) in Shanghai Ruijin Hospital by a group of critical-care clinicians (including a professor, an associate professor, three attending physicians and one resident) and surgeons (a professor and an associate professor).

Fluids for expansion were normal saline (NS) and/or Ringer’s lactate (RL) as well as plasma, 6% hydroxyethyl starch (HES) (200 kD/0.5). Conventional hematological parameters, arterial blood gas, lactate concentration, electrolyte, hepatic and renal functions were analyzed before fluid expansion. Except for disparity of fluid treatment, patients were managed and cared in the same manner, such as Sandostatin administration, gastrointestinal decompression, prophylaxis of antibiotics, clysis using NS and Radix et Rhizoma Rhei (Chinese herb, pored via gastric tube), and topical application of PI XIAO (Traditional Chinese medicine, main components include Na2SO4∙10H2O, sulfur, NaCl and MgSO4).

The treatment response to fluid administration was evaluated every 4 hours on the restoration of circulatory function, which was objectified by heart rate, central venous pressure (CVP) and blood pressure. A positive response included the fulfillment of two or more of four criteria: HR <120 beats/min, MAP 65–85 mm Hg, urine output ≥1 ml∙kg-1∙h-1 and HCT ≤35%. Crystalloid and colloid were infused simultaneously at a 2:1 ratio.

If MAP was less than 60 mm Hg, vasopressors were administered within 30 minutes to achieve a MAP of >70 mm Hg. Thereafter, rate of fluid expansion was performed either rapidly in Group I (fluid infusion rate was 10–15 ml∙kg-1∙h-1) or gradually (fluid infusion rate was 5–10 ml∙kg-1∙h-1) in Group II. Optimal hemodynamics was obtained as rapid as possible in Group I and gradually in Group II through controlled fluid infusion. Immediately after the criteria for fluid expansion were met, body fluid was redistributed by the method of increased colloid infusion to raise plasma osmolality (Ratio of crystalloid and colloid was 1 to 2–3). Figure briefly describes the treatment scheme.


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Figure. Flow chart for patient enrollment and fluid therapy treatment. BLC, blood lactate concentration; UO, urine output; MAP, mean arterial pressure; HR, heart rate; HCT, hematocrit.

Monitoring of biological parameters
Patients′ body temperature, heart rate, urine output, blood pressure, central venous pressure and hematocrit were measured continuously from the admission moment and assessed every 4 hours for 48 hours. Blood lactate concentrations were measured on admission day and when criteria for fluid expansion were met. APACHE II score, amounts of colloid and crystalloid, and mean fluid infusion rate were recorded continuously every 24 hours for 72 hours. The total volume of fluid sequestration was assessed from D0 to 72 h (D3). D0 is the admission day; D1, D2 and D3 are 1st, 2nd, 3rd 24 hours, respectively.

Parameters for prediction on prognosis and complications included rate of mechanical ventilation, incidence of ACS,6 sepsis within 2 weeks and survival rate.7

Statiscal analysis
Measurement and categorical data were expressed as mean ± standard deviation (SD) and percentage, respectively. Differences between the two groups were assessed by Student’s t test for continuous variables or the chi-square test for categorical variables using SPSS 11.0 statistical software. A P <0.05 was considered statistically significant.

RESULTS

Baseline characteristics of patients
No significant difference was found between the two groups in any of the baseline characteristics, including the time interval from onset of symptoms to therapeutic treatment, age, APACHE II score, HCT, heart rate, MAP, blood lactate concentration and urine output (Table 1).


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Table1. Baseline characteristics of the Patients
 
Fluid therapy variables
The amount of crystalloids and colloids in Group I was higher than those of Group II (P <0.05) on D0. No significant difference was found thereafter (P >0.05). No significant difference was found on HCT between the two groups upon admission (P >0.05). At D1, HCT was lower in the group assigned to rapid fluid expansion (P <0.05). Thereafter, no significant difference was found (P >0.05). The total volume of fluids infusion in Group I was not significantly different from Group II at any time of the study. (Table 2)


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Table 2. Characteristics of fluid therapy

Ratio of the total volume fluid administered on D0 and four days was much higher in patients assigned to rapid fluid expansion than those assigned to controlled fluid expansion (P <0.05). Fluid infusion rate was significantly faster in Group I than in Group II on D0 (P <0.05) while it was much slower in Group I at D1 (P <0.05). No significant difference was found on D2 and D3 (P >0.05).

Fluid sequestration volume was significantly higher in patients of Group I than that of patients assigned to controlled fluid expansion during the 4-day study (P <0.05).

Parameters for fluid expansion and prognosis
The time it took to meet the criteria for fluid expansion was significantly shorter in Group I patients (P <0.05). Blood lactate concentrations on admission in Group I ((5.2±3.7) mmol/L) and group II ((5.6±2.9) mmol/L) both decreased to normal levels ((2.0±0.7) and (1.9±1.5) mmol/L, respectively) when criteria for fluid expansion were met (P <0.05). No significant difference was found in APACHE II scores between the two groups on admission (P >0.05). However, APACHE II scores were significantly higher in patients assigned to rapid fluid expansion than patients in Group II (P <0.05) thereafter. (Table 3)


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Table 3. Prognosis variables

The rate of mechanical ventilation and the incidence of ACS were significantly higher in Group I patients than Group II patients (P <0.05). The incidence of sepsis within 2 weeks after onset of the disease was significantly higher in Group I patients than patients assigned to controlled fluid expansion (P <0.05). Survival rate was significantly lower in Group I than Group II (P <0.05). (Table 3)

DISCUSSION

Acute pancreatitis is an unstable disease that causes intravascular fluid loss due to local and systemic inflammation. Clinical improvement can be achieved by fluid infusion. However, acute fluid collection and interstitial edema may arise with ongoing fluid resuscitation in the early phase of SAP. Though response to initial fluid resuscitation is the key to determining therapeutic strategies, the appropriate rate of infusion has not been clearly defined.

In 1968, researchers8 proposed limited fluid resuscitation, which however was disapproved by most physicians. Massive fluid resuscitation on ameliorating pancreatic perfusion and maintaining functional capillary density was not as effective as isovolume hemodilution. Moreover, massive fluid resuscitation could neither inhibit pancreatic ischemia nor decrease oxygen consumption.9-12 Oftentimes, it was complicated with acute lung edema, cerebral edema, abdominal hypertension (abdominal compartment syndrome) and extensive soft tissue edema, which led to abnormal distribution of tissue oxygen resulting in ischemia.13 Recent studies showed that small volume fluid resuscitation (4 ml∙kg-1∙h-1) could ameliorate renal and pulmonary function simultaneously,11 though the treatment strategy has not been optimized.14,15

An ideal fluid resuscitation therapy should both overcome systemic hypovolemia caused by intravascular fluid loss and prevent (or decrease) body fluid sequestration in retroperitoneal spaces, the abdominal cavity and tissue interstitium within 72 hours after onset of symptoms. The peak of SAP mortality is at 72 hours after the disease onset. The heterogeneity of capillary leakage after 72 hours could severely complicate the treatment. Therefore, the period from onset to treatment should be controlled within 72 hours. In our study, the baseline characteristics were similar in the two study groups and the severity of the disease before treatment was comparable. Results showed that the difference of fluid therapy on admission day contributed to the different prognosis in these two groups. Fluid infusion rate and total volume of fluid administered were significantly higher in Group I on D0 than Group II, though the fluid infusion rate was close to the reported value 545 ml/h.16 The total volume of fluid infusion in the first 12 hours accounted for 30% of the total volume in Group I, which was close to the ratio of 37% during a 6-hour fluid resuscitation in a previous study.17 In the controlled fluid expansion group, the ratio was only 20%. The total volume of fluid administered in the two groups during the first four days was near to the reported volume ((11000±4100)ml).18 Therefore, body fluid sequestration during the first 4 days was lower in group II than in group I. Subsequent results demonstrated that both prognosis and complications of the disease were improved significantly in group II.

Rapid reduction of HCT and fluid sequestration were the main outcomes in patients assigned to Group I. Lower HCT could lead to tissue hypoxia caused by the fall of red blood cells passing through pulmonary vasculature. According to results in this study and in Early Goal-directed Therapy (EGDT),17 HCT should be in the range of (30–35)% during fluid expansion. The fluid infusion rate (400 ml/h) in Group I was higher than the reported rate of (250–350)ml/h.18 Large fluid resuscitation could cause fluid sequestration, severe pulmonary interstitial edema, abdominal compartment syndrome, hypothermy, coagulation disorders,19-21 hepatic injury, as well as harmful effects on kidney22 and decreased oxygen extraction13 with the end-result of MODS.23 Thus, even though oxygen delivery can become normal, tissue hypoxia still occurs and oxygen delivery would decrease due to significant reduction of hematocrit. Subsequently, the rate of mechanical ventilation, the incidence of ACS and mortality would significantly increase in patients treated with rapid fluid expansion. Additionally, evidence from rapid fluid expansion in burns (fluid infusion rate of (398.7±105.5)ml/kg in the first 24 h), which showed high incidence of ACS and increased inspiratory pressure and PaCO2,19 also supported our results. Therefore, these data suggested that controlled fluid expansion is a better strategy for fluid expansion in SAP within 72 hours.

Capillary leakage is a complication of SAP. Increased permeability of vessels causes fluid shift to third space during the period of fluid expansion. Elevated liquid collection in third space can lead to higher morbidity of MODS and mortality.24 Although blood volume expansion is the most important management in fluid resuscitation, normal distribution of body fluid in acute response phase is also vital. Our results also demonstrated that increased body fluid sequestration contributed to more complications and higher mortality.

In summary, the principle of fluid therapy, “negative water balance” after the fluid expansion meets the criteria. According to the clinical trial, we propose the strategy of fluid therapy with controlled fluid expansion and restoration of normal body fluid distribution within 72 hours after onset of the disease.


Acknowledgements: We thank all nurses working under Dr. HUANG He and Dr. ZHANG Hong in Department of General Surgery, Shanghai Ruijin Hospital.

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  1. Shanghai Leading Academic Discipline Project,No. S30204;