Superior Survival Outcomes of a Polyethylene Glycol-20k Based Resuscitation Solution in a Preclinical Porcine Model of Lethal Hemorrhagic Shock.

OBJECTIVE: To compare early outcomes and 24-hour survival after LVR with the novel polyethylene glycol-20k-based crystalloid (PEG-20k), WB, or hextend in a preclinical model of lethal HS. BACKGROUND: Posttraumatic HS is a major cause of preventable death. current resuscitation strategies focus on restoring oxygen-carrying capacity (OCC) and coagulation with blood products. Our lab shows that PEG-20k is an effective non-sanguineous, LVR solution in acute models of HS through mechanisms targeting cell swelling-induced microcirculatory failure. METHODS: Male pigs underwent splenectomy followed by controlled hemorrhage until lactate reached 7.5-8.5 mmol/L. They were randomized to receive LVR with PEG-20k, WB, or Hextend. Surviving animals were recovered 4 hours post-LVR. Outcomes included 24-hour survival rates, mean arterial pressure, lactate, hemoglobin, and estimated intravascular volume changes. RESULTS: Twenty-four-hour survival rates were 100%, 16.7%, and 0% in the PEG-20k, WB, and Hextend groups, respectively (P= 0.001). PEG-20k significantly restored mean arterial press, intravascular volume, and capillary perfusion to baseline, compared to other groups. This caused complete lactate clearance despite decreased OCC. Neurological function was normal after next-day recovery in PEG-20k resuscitated pigs. CONCLUSION: Superior early and 24-hour outcomes were observed with PEG-20k LVR compared to WB and Hextend in a preclinical porcine model of lethal HS, despite decreased OCC from substantial volume-expansion. These findings demonstrate the importance of enhancing microcirculatory perfusion in early resuscitation strategies.

Acute resuscitation with polyethylene glycol-20k: A thromboelastographic analysis.

BACKGROUND: Previous ex vivo studies have shown that polyethylene glycol-20,000 Da (PEG-20k), a novel synthetic polymer that is highly effective for resuscitation, has a hypocoagulable effect on human blood. This study's objective was to determine the in vivo effects of PEG-20k-based resuscitation solutions on coagulation and platelet function in a porcine model of hemorrhagic shock. METHODS: Anesthetized pigs underwent controlled hemorrhage until the lactate reached 7 mmol/L or 50% to 55% of their estimated blood volume was removed. A laparotomy was performed to simulate tissue injury. Low volume resuscitation (LVR) was given with fluorescein isothiocyanate-labeled 10% PEG-20k solution (100 mg/mL) or Lactated Ringers, both delivered at volumes equal to 10% of the estimated blood volume (n = 5). Thromboelastography was performed after surgery (baseline), after hemorrhage, and 15 minutes, 120 minutes, and 240 minutes postresuscitation. Hemoglobin was measured to determine changes in plasma volume. Plasma PEG-20k concentration was measured by indicator dilution. RESULTS: Pigs given PEG-20k survived 2.6-fold longer than controls (p < 0.001) and had a significant increase in plasma volume demonstrated by the sustained drop in hemoglobin, relative to controls. Pigs resuscitated with LR died from hypotension an average of 90 minutes after resuscitation compared to the PEG-20k pigs, which all survived 240 minutes and were then euthanized with normal blood pressure and lactate. Administration of PEG-20k primarily decreased the thromboelastograph maximum amplitude, however this began to return toward baseline by 240 minutes. Peak plasma concentration of PEG-20k after LVR were 40% lower than predicted, based on simple dilution (5.7 mg/mL vs. 10 mg/mL) and the half-life was 59.6 minutes. CONCLUSION: These data demonstrate that acute resuscitation with PEG-20k significantly improves tolerance to hypovolemia but also decreases platelet function in the coagulation cascade, which was due, in part, to its volume expanding effects.

Low-volume resuscitation using polyethylene glycol-20k in a preclinical porcine model of hemorrhagic shock.

INTRODUCTION: Polyethylene glycol-20k (PEG-20k) is highly effective for low-volume resuscitation (LVR) by increasing tolerance to the low-volume state. In our rodent shock model, PEG-20k increased survival and expanded the "golden hour" 16-fold compared to saline. The molecular mechanism is largely attributed to normalizations in cell and tissue fluid shifts after low-flow ischemia resulting in efficient microvascular exchange. The objective of this study was to evaluate PEG-20k as an LVR solution for hemorrhagic shock in a preclinical model. METHODS: Anesthetized male Yorkshire pigs (30-40 kg) were hemorrhaged to a mean arterial pressure (MAP) of 35 to 40 mm Hg. Once lactate reached 7 mmol/L, either saline (n = 5) or 10% PEG-20k (n = 5) was rapidly infused at 10% calculated blood volume. The primary outcome was LVR time, defined by the time from LVR administration to the time when lactate again reached 7 mmol/L. Other outcomes measured included MAP, heart rate, cardiac output, mixed venous oxygen saturation, splanchnic blood flow, and hemoglobin. RESULTS: Relative to saline, PEG-20k given after controlled hemorrhage increased LVR time by 16-fold, a conservative estimate given that the lactate never rose after LVR in the PEG-20k group. Survival was 80% for PEG-20k LVR compared to 0% for the saline controls (p < 0.05). Polyethylene glycol-20k also significantly decreased heart rate after hemorrhage and increased cardiac output, MAP, splanchnic flow, and mixed venous oxygen saturation. Falling hemoglobin concentrations suggested sizable hemodilution from fluid shifts into the intravascular compartment. CONCLUSIONS: In a preclinical model of controlled hemorrhagic shock, PEG-20k-based LVR solution increased tolerance to the shock state 16-fold compared to saline. Polyethylene glycol-20k is a superior crystalloid for LVR that may increase safe transport times in the prehospital setting and find use in hospital emergency departments and operating rooms for patients awaiting volume replacement or normalization of cell, tissue, and compartment fluid volumes.

Amplified cytokine response and lung injury by sequential hemorrhagic shock and abdominal compartment syndrome in a laboratory model of ischemia-reperfusion.

BACKGROUND: Increased intra-abdominal pressure has been shown to result in a myriad of physiologic aberrations that result in the abdominal compartment syndrome (ACS). The clinically relevant combination of hemorrhagic shock and resuscitation and subsequent ACS, however, has not been studied in detail. We hypothesized that sequential hemorrhagic shock (HS) and ACS would result in greater cytokine activation and polymorphonuclear neutrophil (PMN)-mediated lung injury than with either insult alone. METHODS: Twenty Yorkshire swine (20-30 kg) were studied. Group 1 (n = 5) was hemorrhaged to a mean arterial pressure of 25 to 30 mm Hg for 60 minutes and resuscitated to baseline mean arterial pressure. Intra-abdominal pressure was then increased to 30 mm Hg above baseline and maintained for 60 minutes. Group 2 (n = 5) was subjected to HS alone and Group 3 (n = 5) to ACS alone. Group 4 (n = 5) had sham experiment without HS or ACS. Central and portal venous interleukin-1beta, interleukin-8, and tumor necrosis factor-alpha levels were serially measured. Bronchoalveolar lavage (BAL) for protein and PMNs was performed at baseline and 24 hours after resuscitation. Lung myeloperoxidase was evaluated at 24 hours after resuscitation. RESULTS: Portal and central vein cytokine levels were equivalent but were significantly higher in Group 1 than in other groups. BAL PMNs were higher (p < 0.05) in Group 1 (4.1 +/- 2.0 x 106) than in the other groups (0.6 +/- 0.5, 1.4 +/- 1.3, and 0.1 +/- 0.0 x 106, respectively) and lung myeloperoxidase activity was higher (p < 0.05) in Group 1 (134.6 +/- 57.6 x 106/g) than in the other groups (40.3 +/- 14.7, 46.1 +/- 22.4, and 7.73 +/- 4.4 x 106/g, respectively). BAL protein was higher (p < 0.01) in Group 1 (0.92 +/- 0.32 mg/mL) compared with the other groups (0.22 +/- 0.08, 0.29 +/- 0.11, and 0.08 +/- 0.06 mg/mL, respectively). CONCLUSION: In this clinically relevant model, sequential insults of ischemia-reperfusion (HS and resuscitation) and ACS were associated with significantly increased portal and central venous cytokine levels and more severe lung injury than HS or ACS alone.