Plasma Resuscitation Improved Survival in a Cecal Ligation and Puncture Rat Model of Sepsis

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d578984e167">Background</h5> <p id="P1">The paradigm shift from crystalloid to plasma resuscitation of traumatic hemorrhagic shock has improved patient outcomes due in part to plasma-mediated reversal of catecholamine and inflammation-induced endothelial injury, decreasing vascular permeability and attenuating organ injury. Since sepsis induces a similar endothelial injury as seen in hemorrhage, we hypothesized that plasma resuscitation would increase 48-hour survival in a rat sepsis model. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d578984e172">Methods</h5> <p id="P2">Adult male Sprague-Dawley rats (375–425g) were subjected to 35% cecal ligation and puncture (CLP) (t=0h). Twenty-two hours post-CLP and prior to resuscitation (t=22h), animals were randomized to resuscitation with normal saline (NS, 10 cc/kg/hr) or pooled rat fresh frozen plasma (FFP, 3.33 cc/kg/hr). Resuscitation under general anesthesia proceeded for the next six hours (t=22h to t=28h); lactate was checked every 2 hours, and fluid volumes were titrated based on lactate clearance. Blood samples were obtained before (t=22 h) and after resuscitation (t=28 h), and at death or study conclusion. Lung specimens were obtained for calculation of wet-to-dry weight ratio. Fisher’s exact test was used to analyze the primary outcome of 48-hour survival. ANOVA with repeated measures was used to analyze the effect of FFP versus NS resuscitation on blood gas, electrolytes, blood urea nitrogen (BUN), creatinine, interleukin (IL)-6, IL-10, catecholamines, and syndecan-1 (marker for endothelial injury). A two-tailed alpha level of <0.05 was used for all statistical tests. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d578984e177">Results</h5> <p id="P3">Thirty-three animals were studied: 14 FFP, 14 NS, and 5 sham. Post-CLP but pre-resuscitation (t=22 h) variables between FFP and NS animals were similar and significantly deranged compared to sham animals. FFP significantly increased 48-hour survival compared to NS (n=8 [57%] vs n=2 [14%]), attenuated the post-resuscitation (t=28 h) levels of epinephrine (mean 2.2 vs 7.0 ng/ml), norepinephrine, (3.8 vs 8.9 ng/ml), IL-6 (3.8 vs 18.7 ng/ml), and syndecan-1 (21.8 vs 31.0 ng/ml) (all p<0.05), improved the post-resuscitation PO <sub>2</sub> to FiO <sub>2</sub> ratio (353 vs 151), and reduced the pulmonary wet-to-dry weight ratio (5.28 vs 5.94) (all p<0.05). </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d578984e188">Conclusion</h5> <p id="P4">Compared to crystalloid, plasma resuscitation increased 48-hour survival in a rat sepsis model, improved pulmonary function and decreased pulmonary edema, and attenuated markers for inflammation, endothelial injury, and catecholamines. </p> </div>

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Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.

Tim Jansen, Jasper van Bommel, F Jeanette Schoonderbeek … (2010)

It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves outcome. To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU) patients admitted with a lactate level of greater than or equal to 3.0 mEq/L. Patients were randomly allocated to two groups. In the lactate group, treatment was guided by lactate levels with the objective to decrease lactate by 20% or more per 2 hours for the initial 8 hours of ICU stay. In the control group, the treatment team had no knowledge of lactate levels (except for the admission value) during this period. The primary outcome measure was hospital mortality. The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat population (348 patients), hospital mortality in the control group was 43.5% (77/177) compared with 33.9% (58/171) in the lactate group (P = 0.067). When adjusted for predefined risk factors, hospital mortality was lower in the lactate group (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87; P = 0.006). In the lactate group, Sequential Organ Failure Assessment scores were lower between 9 and 72 hours, inotropes could be stopped earlier, and patients could be weaned from mechanical ventilation and discharged from the ICU earlier. In patients with hyperlactatemia on ICU admission, lactate-guided therapy significantly reduced hospital mortality when adjusting for predefined risk factors. As this was consistent with important secondary endpoints, this study suggests that initial lactate monitoring has clinical benefit. Clinical trial registered with www.clinicaltrials.gov (NCT00270673).

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The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks.

John Holcomb, Deborah J Del Junco, Erin E Fox … (2013)

To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios. Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models. Ten US level I trauma centers. Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group). In-hospital mortality. Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P < .001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBCs (adjusted hazard ratio = 0.31; 95% CI, 0.16-0.58) and platelets:RBCs (adjusted hazard ratio = 0.55; 95% CI, 0.31-0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from nonhemorrhagic causes prevailed. Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.

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Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte.

Andrew Shaw, Sean Bagshaw, Stuart Goldstein … (2012)

To assess the association of 0.9% saline use versus a calcium-free physiologically balanced crystalloid solution with major morbidity and clinical resource use after abdominal surgery. 0.9% saline, which results in a hyperchloremic acidosis after infusion, is frequently used to replace volume losses after major surgery. An observational study using the Premier Perspective Comparative Database was performed to evaluate adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery. The primary outcome was major morbidity and secondary outcomes included minor complications and acidosis-related interventions. Outcomes were evaluated using multivariable logistic regression and propensity scoring models. For the entire cohort, the in-hospital mortality was 5.6% in the saline group and 2.9% in the balanced group (P < 0.001). One or more major complications occurred in 33.7% of the saline group and 23% of the balanced group (P < 0.001). In the 3:1 propensity-matched sample, treatment with balanced fluid was associated with fewer complications (odds ratio 0.79; 95% confidence interval 0.66-0.97). Postoperative infection (P = 0.006), renal failure requiring dialysis (P < 0.001), blood transfusion (P < 0.001), electrolyte disturbance (P = 0.046), acidosis investigation (P < 0.001), and intervention (P = 0.02) were all more frequent in patients receiving 0.9% saline. Among hospitals in the Premier Perspective Database, the use of a calcium-free balanced crystalloid for replacement of fluid losses on the day of major surgery was associated with less postoperative morbidity than 0.9% saline.