February 2023

This unblinded superiority trial found that restrictive fluids with early prioritization of pressors was non-inferior to liberal fluid administration during the first 24 hours of treating sepsis-induced hypotension.

Summary: Intravenous fluid administration is a critical component in the early management of sepsis. However, the data supporting liberal versus restrictive fluid administration is dynamic and some observational studies suggest restrictive fluid strategies may be superior. The 2021 Surviving Sepsis Guidelines even downgraded the recommendation of providing 30 ml/kg of fluid over the first 3 hours of resuscitation from “strong” to “weak” due to “low quality of evidence.” The investigators of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial set out to directly compare fluid strategies during the first 24 hours of resuscitation in patients diagnosed with sepsis who were refractory to initial treatment with 1-3L of fluid. Upon identification, these patients were randomized to a “liberal” versus “restrictive” fluid protocol. Specifically, the “liberal” protocol included an initial 1-2L bolus of isotonic crystalloid followed by fluid boluses based on clinical endpoints such as tachycardia with “rescue” pressors allowed for certain indications or after administration of 5L of fluid. The “restrictive” group prioritized vasopressors as the primary treatment after the initial boluses. “Rescue” fluids were allowed for prespecified triggers that suggested volume depletion or if felt in best interest of the patient. Additional protocol details can be found here. Primary outcomes included death before discharge home or before day 90 and secondary outcomes included days free from ventilator, free from CRRT, free from vasopressor use, out of ICU, and out of hospital. 

Authors found no difference in mortality between the two groups of patients treated with restrictive versus liberal fluid strategies during their first 24 hours in the hospital. Further, there were no differences between the secondary outcomes such that the study was halted at 1563 patients at the recommendation of the data safety and monitoring board. Examining the actual differences in the amount of fluid received by each group, the difference in medians was 1800mL (500 vs. 2300mL) and 2134mL (1267 vs. 2400mL) at 6 and 24 hours respectively. Patients in the restrictive group were more likely to be treated with vasopressors as expected (59% vs. 37%) and be given pressors earlier and for a longer duration of time with no observed adverse outcomes. One intriguing observation was that the protocol allowed for the early administration of vasopressors through a peripheral IV. For the 500 patients who received pressors through a peripheral IV, only 3 experienced an adverse event – extravasations that resolved upon cessation of infusion without additional intervention or clinical consequence. This suggests prioritizing vasopressor administration early in the management of sepsis even when the only access is a peripheral IV is a safe strategy.

Overall these results are in line with prior studies including the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trials which explored the utility of restrictive versus standard fluids strategies. A notable difference between these studies was that the CLASSIC trial included patients who had received care in the hospital prior to admission to the ICU (34%) including many already requiring a trip to the OR (23%). In contrast, the CLOVERS Trial recruited patients upon presentation to the hospital, the majority of which were in the ED, and even excluded patients requiring immediate operative intervention. The study makes little mention of the patients’ eventual operative needs, if any – important considerations when translating the results to our surgical populations. However, this limitation combined with noninferiority results of this, and the CLASSIC trial, may lead to future studies exploring the optimal fluid versus pressor strategy in specific surgical patient populations. 

This randomized controlled trial evaluated liver transplant outcomes after use of normothermic machine perfused grafts in comparison to ischemic cold storage grafts. Use of normothermic machine-perfused liver grafts was associated with significantly lower rates of early allograft dysfunction.

Summary: The PROTECT trial aimed to evaluate whether the use of oxygenated portable normothermic perfusion of deceased donor livers (Organ Care System, or OCS) could improve outcomes compared with the current standard of care using ischemic cold storage (ICS). In this study, a prospective multicenter randomized clinical trial, 429 patients were enrolled between November 2016 and October 2019, of which 300 patients were randomly assigned to receive a donor liver preserved by either normothermic perfusion or conventional ischemic cold storage. The as-treated population consisted of 299 patients, of which 153 were included in the OCS Liver group and 146 in the ICS group. After protocol violations were removed, the per-protocol population consisted of 293 patients, with 151 in the OCS Liver group and 142 in the ICS group. The primary effectiveness endpoint was the incidence of early allograft dysfunction (EAD), and the primary safety endpoint was the number of liver graft-related severe adverse events within 30 days after transplant.
 
This trial demonstrated that the use of the OCS Liver was both noninferior and superior to the ICS group in both the per-protocol population and the modified intention-to-treat analysis population. The OCS Liver was associated with a significant decrease in the incidence of EAD compared with ICS in the primary analysis per-protocol population (18% vs 31%, P=0.01). The effect was further validated by histopathologic assessment of liver graft biopsies after reperfusion. The OCS Liver was associated with significantly less lobular inflammation, a marker of ischemia-reperfusion injury, compared to ICS. On the other hand, portal inflammation, a histologic marker not associated with ischemia-reperfusion injury, was similar between groups. By stratifying all trial recipient outcomes by presence or absence of EAD, the study found that EAD was associated with significantly higher risk of graft failure compared with no EAD, significantly longer ICU stay, and significantly longer overall hospital stay.
 
The OCS Liver group had improved patient survival rates and decreased biliary complications 6 and 12 months after transplant, compared to the ICS group (P = .02 for both time points). Patient survival at day 30 after transplant was 99.3% for the OCS Liver group and 99.3% for the ICS group. The OCS Liver also allowed for continuous monitoring of lactate levels, bile production, and hepatic artery and portal vein pressures and flows throughout preservation. Reperfusion syndrome was reported to be more severe in the ICS group, as evidenced by higher recipient lactate levels at approximately 120 minutes after reperfusion (P = .046). There was no difference in the incidence of anastomotic nonischemic biliary complications between the groups. Overall 12-month patient survival was 94.0% for the OCS Liver group and 93.7% for the ICS group. The PROTECT trial also met its safety end point, with the mean number of LGRSAEs within the initial 30 days after transplant for the OCS Liver (0.046 per patient) noninferior to ICS (0.075 per patient).

Limitations of this paper include the short interval period for follow-up (30 days or discharge from the hospital admission for transplantation) and inability to blind providers to the control or experimental group (though this was mitigated by randomization after organs were accepted).  This study was also limited by exclusion criteria which may not be representative of all transplant centers’ current clinical practices (e.g. exclusion of donors with DCD livers >55 years or livers requiring accessory vessel reconstruction, or exclusion of recipients with acute or fulminant liver failure, chronic kidney failure, multiorgan transplant, or hemodynamic compromise). 

While this study’s results show normothermic machine perfusion to be a superior modality to ischemic cold storage, one must exercise caution when making inferences on wide-scale adoption. The inherent complexity of OCS liver, relative to ICS, pose additional practical challenges. These outcomes suggest that increased adoption of normothermic machine perfusion preservation may reduce posttransplant complications with deceased donor livers, and potentially increase the pool of available or usable deceased donor liver grafts. Transdisciplinary investigation of its cost effectiveness may provide further incentives regarding its purported benefit when carried over into real patient care.

This retrospective cohort analysis used a propensity matched cohort of traumatic hemorrhage patients in the United States to evaluate differences in outcomes between those that received cryoprecipitate and fibrinogen concentrate.

Summary: Development of acute coagulopathy is a major complicating factor in the traumatic hemorrhage population. It is attributed the lethal triad (acidosis, hypothermia, and loss of coagulation factors) and associated with a four-fold increase in mortality. Resuscitation in this setting requires rapid and balanced blood product administration, hemostatic resuscitation methods and early, rapid replacement of coagulation factors. Fibrinogen is the final factor in the formation of a stable fibrin clot, and one the earliest factors to be diminished in a major bleed; replacement can be achieved with either fibrinogen concentrate or cryoprecipitate.

This was a retrospective cohort study of the American College of Surgeons Trauma Quality Improvement Program (TQIP) database. The subjects were adult (age 18 and older) trauma patients, from over 800 trauma centers across the United States, with the majority being level I and level II centers (57% and 25%, respectively). Of over 6000 patients that met inclusion criteria, 255 were ultimately in the matched cohort with 85 receiving fibrinogen concentrate and 170 receiving cryoprecipitate. The primary and secondary outcomes were 24-hour blood product transfusion requirements time to first fibrinogen product administration.

The study found that those in the fibrinogen concentrate group received significantly lower amounts of pRBC, FFP, and platelets within the first 24hours, had shorter hospital and ICU length of stay, but no difference in mortality. The fibrinogen concentrate group also had shorter time to fibrinogen administration. Interestingly, the blood product requirement findings were contrary to the Fibrinogen Early in Trauma Study, a smaller prospective study.

Presented is an important contribution to trauma resuscitation literature, that may drive better resource utilization and improve patient outcomes. While fibrinogen concentrate is significantly more expensive than cryoprecipitate, the costs and resources saved with reduced blood product administration, hospital and ICU stays, may suggest a bigger role for fibrinogen concentrate in the hemorrhagic Trauma setting.