Early goal-directed fluid therapy with fresh frozen plasma reduces severe acute pancreatitis mortality in the intensive care unit

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Abstract

Hemodynamic instability plays a major role in the pathogenesis of systemic inflammation, tissue hypoxia, and multiple organ dysfunction syndrome associated with severe acute pancreatitis (SAP). Aggressive fluid replacement is one of the key interventions for the hemodynamic support in severe acute pancreatitis.1 Although the need for fluid resuscitation in severe pancreatitis is well established, the goals and components of this treatment are still a matter of debate. We used resuscitation strategies according to early goaldirected therapy (EGDT); we measured the effects of these volume resuscitation on clinical outcomes such as organ function and mortality. Because frozen plasma is cheaper and more easily acquired than albumin for patients, we hypothesized that fluid resuscitation with frozen plasma according to EGDT would be associated with reduced incidence of organ failure and mortality as compared with individuals resuscitated with normal crystalloid and plasma substitute volume resuscitation. METHODS Patient eligibility From September 2008 to September 2012 eligible patients meeting the Atlanta criteria of diagnosis for SAP admitted to the department of Intensive Care Unit in Wuxi Second People's Hospital were enrolled within 24 hours after onset of the disease. Exclusion criteria included any of the following: sepsis, less than 18 or more than 70 years of age, pregnant, chronic heart disease, pacemaker installed, chronic renal failure and SAP with unknown etiology. Two hundred patients were enrolled in the study. Etiologies were gallstone (105 cases), hyperlipidemia (25 cases), alcoholism (50 cases), and others (20 cases). Patients were randomly assigned to a Control group (n=68), EGDT group 1 (n=64), or EGDT group 2 (n=68). Treatments of SAP Except for the disparity of fluid treatment, all patients were all managed and cared for in the same manner according to Practice Guidelines in Acute Pancreatitis;2 including supportive care, enteral feeding, treatment of sterile pancreatic necrosis, treatment of associated pancreatic duct disruptions, and use of antibiotics. The Control group (n=68) was treated with crystalloid resuscitation (Ringer's lactate and normal saline) and 6% hydroxyethyl starch130/0.42 for resuscitation according to the guideline. The adequacy of fluid resuscitation should be monitored by vital signs, urinary output and a decrease of the hematocrit at 12 hours after admission. The EGDT group 1 (n=64) were resuscitated with crystalloid solution (Ringer's lactate and normal saline) and 6% hydroxyethyl starch 130/0.42 according to EGDT protocol. The EGDT group 2 (n=68) were resuscitated with crystalloid volume (Ringer's lactate and normal saline), 6% hydroxyethyl starch 130/0.42 and two units of frozen plasma according to EGDT protocol, two units of frozen plasma was used as well as daily in next two days. Two units of frozen plasma were infused within 6 hours. Crystalloid and colloid were infused simultaneously at a 2:1 ratio. The objective of fluid therapy in the EGDT groups according to protocol: During the first 6 hours of resuscitation, the goals of initial resuscitation should include all of the following; central venous pressure (CVP) 8-12 mmHg, mean arterial pressure ≥65 mmHg, urine output ≥0.5ml·kg−1·h−1, and central venous (superior vena cava) or mixed venous oxygen saturation ≥70%. Follow-up of patients continued for 28 days after discharge. Most data are expressed as mean ± standard deviation (SD) and percentage. Differences between the three groups were assessed by analysis of variance (ANOVA) test for continuous variables or the chi-square test for categorical variables using SPSS 13.0 statistical software. A P-value less than 0.05 was considered statistically significant. RESULTS Primary clinical outcomes within 28 days Primary clinical outcomes are shown in Table 1. Patients in the control group had a higher rate of in-hospital mortality than was seen in EGDT group 1 and group 2 (23.5 vs. 21.9 and 17.6%, P<0.05), abdominal compartment syndrome (ACS) (26.5 vs. 21.9 and 17.6%, P<0.03) and multiple organ dysfunction syndrome (MODS)(29.4 vs. 26.5 and 23.5%, P<0.05) were also higher in the control group than in the EGDT groups. Patients in the EGDT group 1 had a higher rate of in-hospital mortality than patients in EGDT group 2 (21.9 vs. 17.6%, P<0.05), and significantly higher rates of ACS (21.9 vs. 17.6%, P<0.03) and MODS (26.5 vs.23.5%, P<0.05) within the first 28 days of hospitalization. The days of ventilation and hospitalization in the ICU was longer in the control group than in EGDT groups 1 and 2 (15.3±5.2 vs.12.3±4.2 and 10.3±4.4, P<0.05 and 20.6±6.8 vs. 18.6±6.3, 15.4±4.7, P<0.05) and ventilation and hospitalization days were significantly longer in EGDT group 1 than in EGDT group 2 (12.3±4.2 vs. 10.3±4.4, P<0.05 and 18.6±6.3 vs. 15.4±4.7 P<0.05).Table 1: Primary clinical outcomes within 28 daysSecondary clinical outcomes in 72 hours Patients in the control group had a higher APACHE II scores than patients in EGDT groups 1 and 2 (15.5±2.2 vs. 14.9±2.6 and 10.3±4.4, P<0.05) and a lower PaO2/FiO2 ratio (258±8.2 vs. 272±9.3 and 305±10.0 P<0.05). Patients in the EGDT group 1 had significantly higher APACHE II scores (14.9±2.6 vs. 10.3±4.4, P<0.05) and a significantly lower PaO2/FiO2 ratio (272±9.3 vs. 305±10.0, P<0.05) than patients in EGDT group 2. Amount of total fluid intake and fluid balance within 3 days The control group and EGDT group 1 received more intravenous fluid resuscitation daily over three days compared to the EGDT group 2; there were differences between the control group and the EGDT group 1 only on day one (P<0.05). There was a more positive fluid balance in resuscitation and cumulative fluid over three days in the control group and EGDT group 1 compared to EGDT group 2. The fluid accumulation had a negative balance at day three only in EGDT group 2. DISCUSSION The criteria and targets of fluid management in severe acute pancreatitis are controversial. We conducted a prospective feasibility trial assessing the role of goal-directed fluid resuscitation with fresh frozen plasma in acute severe pancreatitis according to EGDT based on guidelines of the Surviving Sepsis Campaign.3 In our study, the crystalloid solution group received more intravenous fluid resuscitation daily compared to the EGDT group with frozen plasma. Lung dysfunction, reflected in impaired oxygenation index and mechanics, were greatly improved in the EGDT group, especially in the frozen plasma group. It is conceivable that the high crystalloid volume can promote vascular leak and interstitial edema; this effect would be reduced using resuscitation with frozen plasma which is not as permeable through the microcirculation of lung compared with crystalloid. There was a noticeable difference in the amount of fluids used between EGDT groups and the control group at the first 24 hours, which may suggest that aggressive intravenous fluid resuscitation in the first six hours, can decrease the amount of fluid resuscitation in the first 24 hours. Our study found that cumulative daily fluid within 72 hours was greater with resuscitation with crystalloid than with frozen plasma in the EGDT groups, and positive fluid balance was greater in the crystalloid resuscitation group than in the frozen plasma group. A positive fluid balance is among the strongest prognostic factors for death, a more positive fluid balance both early in resuscitation and the cumulative fluid balance over four days is associated with an increased risk of mortality during septic shock. The most prominent finding of our study was that the duration of mechanical ventilation and admission in ICU, ACS, MODS and mortality were lower in EGDT group 2 than in the control group. This may be due to the frozen plasma solution resulting in higher cardiac output, oxygen delivery, and lower blood lactate levels than Ringer's lactate. In conclusion, we found that early goal-directed therapy with fresh frozen plasma shortens the duration of positive fluid balance, decreases the amount of positive fluid balance within 72 hours, reduces the duration of mechanical ventilation and admissions to the ICU, and improves PaO2/FiO2 and mortality in severe acute pancreatitis.

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