Effect of Therapeutic Hypothermia on Physiologic, Histologic and Metabolomic Markers of Lung Injury in Experimental Acute Respiratory Distress Syndrome

Abstract

Background Acute respiratory distress syndrome (ARDS) is a severe lung injury characterized by noncardiogenic pulmonary edema and rapid hypoxic respiratory failure. Therapeutic hypothermia improves outcomes of traumatic brain injury and cardiac injuries; however, it has not been widely used or studied in ARDS. Hypothermia may be helpful in reducing injury and inflammation associated with ARDS by reducing pro-inflammatory molecule production. Objective To evaluate the effect of therapeutic hypothermia on the development of injury and inflammation in experimental, short-term ARDS. Hypothesis Hypothermia induced at the onset of lung injury would mitigate histological and serum metabolic changes, as well as changes in respiratory elastance (E) and resistance (R). Methods The Animal Research Committee of the University of British Columbia approved all experimental procedures. Twenty female Yorkshire pigs were divided into 4 groups (n= 5 per group): normothermic control (C), normothermic injured (I), hypothermic control (HC), and hypothermic injured (HI). ARDS was induced via intrapulmonary injection of oleic acid. Hypothermia was induced with a cooling catheter placed into the left jugular vein. The normothermic groups had core temperatures maintained at 36.5-38°C and the hypothermic groups were cooled to 32°C. Animals were euthanized after a 12-hour follow-up period. Respiratory mechanical variables were quantified based the measurements of flow, airway pressure, and esophageal pressure. Tissue samples from the right diaphragmatic lobe were collected after euthanasia and examined for injury score. Plasma samples were collected and 1H-NMR spectroscopy analysis was performed to determine metabolite concentration. Results Therapeutic hypothermia reduced injury in the HI vs. I group (injury score= 0.51±0.18 vs. 0.76±0.06; p<0.05). All cohorts expressed distinct phenotypes with the HI cohort having a reduction in inflammatory metabolites (i.e., succinate) compared to the I cohort. Changes to respiratory mechanics were due to changes in lung E and R (ΔE from pre-injury= 45.55±14.17 cmH2O·l-1; ΔR from pre-injury= 3.07±1.99 cmH2O·l-1·s-1, p<0.05) and not chest-wall E and R (ΔE from pre-injury= 0.73±1.59 cmH2·l-1; ΔR from pre-injury= 0.59±0.14 cmH2O·l-1s-1, p>0.05), with trends for the HI group to have a lower lung R (p=0.99) and E (p=0.93) compared to the I group. Control groups showed no significant change in respiratory mechanics. Conclusion Therapeutic hypothermia canreduce some markers of injury and inflammation associated with ARDS. Further studies are required to determine the effect on longer term outcomes and mortality.