A Toolbox to Investigate the Impact of Impaired Oxygen Delivery in Experimental Disease Models

Abstract

Impaired oxygen utilization is the underlying pathophysiological process in different shock states. Clinically most important are septic and hemorrhagic shock, which comprise more than 75% of all clinical cases of shock. Both forms lead to severe dysfunction of the microcirculation and the mitochondria that can cause or further aggravate tissue damage and inflammation. However, the detailed mechanisms of acute and long-term effects of impaired oxygen utilization are still elusive. Importantly, a defective oxygen exploitation can impact multiple organs simultaneously and organ damage can be aggravated due to intense organ cross-talk or the presence of a systemic inflammatory response. Complexity is further increased through a large heterogeneity in the human population, differences in genetics, age and gender, comorbidities or disease history. To gain a deeper understanding of the principles, mechanisms, interconnections and consequences of impaired oxygen delivery and utilization, interdisciplinary preclinical as well as clinical research is required. In this review, we provide a “tool-box” that covers widely used animal disease models for septic and hemorrhagic shock and methods to determine the structure and function of the microcirculation as well as mitochondrial function. Furthermore, we suggest magnetic resonance imaging as a multimodal imaging platform to noninvasively assess the consequences of impaired oxygen delivery on organ function, cell metabolism, alterations in tissue textures or inflammation. Combining structural and functional analyses of oxygen delivery and utilization in animal models with additional data obtained by multiparametric MRI-based techniques can help to unravel mechanisms underlying immediate effects as well as long-term consequences of impaired oxygen delivery on multiple organs and may narrow the gap between experimental preclinical research and the human patient.

Effects of remote ischemic preconditioning on early markers of intestinal injury in experimental hemorrhage in rats

“…However, medical treatment relied on indirect variables to monitor microvascular oxygen delivery, tissue perfusion and cell integrity. Therefore, the invention and development of devices thought to investigate microcirculation directly were a cornerstone of modern intensive care research 23 . Trzeciak et al reported an improvement of microvascular flow in septic patients to be associated with a decrease in multi-organ failure after 24 h despite the registration of similar macrocirculatory variables 24 .…”

“…Those findings are in accordance with previous observations from our working group 28 . Finally, perfusion markers are reproducibly capable for microvascular monitoring in hemorrhagic sheep, dogs and rats and independent of the modus of shock induction 23 . In 2018 an expert group from the Cardiovascular Dynamics Section of the European Society of Intensive Care Medicine published a second consensus paper with recommendation how to evaluate the microcirculation in critically ill patients 29 .…”

“…As described previously 23 , intestinal tissue was harvested at the end of the experiments, placed in 4 °C isolation buffer (200 mM mannitol, Carl Roth GmbH, Karlsruhe, Germany; 50 mM sucrose Carl Roth GmbH, Karlsruhe, Germany; 5 mM KH 2 PO 2 Merck, Darmstadt, Germany; 5 mM 3-( N -morpholino)-propanesulfonic acid (3-MOPS) Carl Roth GmbH, Karlsruhe, Germany; 0.1% bovine serum albumin BSA, Sigma-Aldrich Corporation, St. Louis, USA; 1 mM ethylene glycol-bis-(beta-aminoethylether)-tetraacetic acid (EGTA), Carl Roth GmbH, Karlsruhe, Germany, pH 7.15) and cleaned gently from faeces and mucus. After incubation with 0.05% trypsin for 5 min to decompose interstitial components, samples were transferred into an isolation buffer containing protease inhibitors (Complete™ Protease Inhibitor Cocktail, Roche Life Science, Mannheim, Germany) and 2% BSA.…”

Local carbachol application induces oral microvascular recruitment and improves gastric tissue oxygenation during hemorrhagic shock in dogs

“…Then, continuous drug infusion was started. After thirty minutes of observation, a fixed-volume hemorrhage was inducted by removing 20% of the estimated total blood volume within 5 min duration via an intravenous peripheral cannula and the arterial catheter ( 40 ). According to Advanced Trauma Life Support (ATLS) shock classification, this represents a class II shock ( 41 ).…”