Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

Abstract

Objective To determine the role of cell swelling in severe hemorrhagic shock and resuscitation injury. Summary Background Data Circulatory shock induces the loss of energy dependent volume control mechanisms. As water enters ischemic cells, they swell, die, and compress nearby vascular structures, which further aggravates ischemia by reducing local microcirculatory flow and oxygenation. Loading the interstitial space with cell impermeant molecules prevents water movement into the cell by passive biophysical osmotic effects, which prevents swelling injury and no-reflow. Methods Adult rats were hemorrhaged to a pressure of 30–35 mm Hg, held there until the plasma lactate reached 10 mM, and given a low volume resuscitation (LVR) (10–20% blood volume) with saline or various cell impermeants (sorbitol, raffinose, trehalose, gluconate, and Polyethylene glycol-20k (PEG-20k). When lactate again reached 10 mM following LVR, full resuscitation was started with crystalloid and red cells. One hour after full resuscitation, the rats were euthanized. Capillary blood flow was measured by the colored microsphere technique. Results Impermeants prevented ischemia-induced cell swelling in liver tissue and dramatically improved LVR outcomes in shocked rats. Small cell impermeants and PEG-20k in LVR solutions increased tolerance to the low flow state by 2 and 5 fold, respectively, normalized arterial pressure during LVR, and lowered plasma lactate after full resuscitation, relative to saline. This was accompanied by higher capillary blood flow with cell impermeants. Conclusions Ischemia-induced lethal cell swelling during hemorrhagic shock is a key mediator of resuscitation injury, which can be prevented by cell impermeants in low volume resuscitation solutions.

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

“…The rodent model of severe hemorrhagic shock was translated to a parallel porcine model for pre-clinical testing of novel PEG-20k based resuscitation solutions (8;9). There are some differences between the two models.…”

“…Since no further bleeding or loss of RBCs was allowed to occur after the end of hemorrhage (because it was a controlled bleed model), the hemoglobin concentration reduction likely represents a proportional dilution effect with non-hemoglobin containing fluid from outside of the vascular compartment. The remaining 50% non-dilutional drop in plasma lactate that was observed after PEG-20k LVR likely represents a combination of clearance by renal filtration into the urine and by the metabolic oxidation of lactate to pyruvate by LDH as the peripheral microcirculation opens (8;9) and aerobic metabolism resumes.…”

“…If lactate decreased and did not reach the target of 7–8 mM/L by 240 minutes, the maximum LVR time was arbitrarily set at 240 minutes. The LVR time is a surrogate for tolerance to the low volume or shock state (8;9). Clinically, it would be similar to the length of time that a patient can safely remain in the low volume state until definitive care and full resuscitation are needed, i.e.…”

“…Parrish et al have demonstrated reduced ischemia-induced cell swelling, increased tolerance to the low volume state, improved capillary blood flow, and higher survival with administration of a low volume solution containing polyethylene glycol-20k (PEG-20k) compared to saline in a rodent model of severe hemorrhagic shock (8;9). The resuscitation effects were extraordinary in this model.…”

Thromboelastographic analysis of novel polyethylene glycol based low volume resuscitation solutions

“…To test resuscitation outcomes of LVR solutions specifically for comparison with TEG outcomes in the dose response series of experiments, a standard rat lactate controlled model of severe hemorrhagic shock with low volume resuscitation was used as previously described in great detail elsewhere [ 2 , 9 , 10 ]. These studies were approved by the VCU IACUC and followed the ARRIVE guidelines [ 14 ].…”