ALM Fluid Therapy Leads to 72 hr Survival After Hemorrhagic Shock
a Model for Studying Differential Gene Expression and Extending Biological Time
Letson, Hayley L., PhD; Morris, Jodie, PhD; Biros, Eric, PhD; Dobson, Geoffrey P., PhD

Journal of Trauma and Acute Care Surgery: May 31, 2019 - Volume Publish Ahead of Print - Issue - p
doi: 10.1097/TA.0000000000002397
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Background Non-compressible torso hemorrhage is a leading cause of traumatic death. Our aim was to examine survival time and the expression of key master genes of cellular metabolism after 3% NaCl adenosine, lidocaine and Mg2+ (ALM) bolus and 4hr 0.9% NaCl/ALM ‘drip’ in a rat model of uncontrolled hemorrhagic shock.

Methods Male Sprague-Dawley rats (425±8g) were anesthetized and randomly assigned to saline controls (n=10) or ALM therapy (n=10). Hemorrhage was induced by liver resection (60% left lateral lobe). After 15min, a single intravenous bolus of 3% NaCl ± ALM (0.7ml/kg) was administered (Phase 1), and after 60min, a 0.9% NaCl ± ALM stabilization ‘drip’ (0.5ml/kg/hour) was infused for 4hrs (Phase 2) with 72hr monitoring. Mean arterial pressure and lactate were measured. After 72hrs (or high moribund score), tissues were freeze-clamped and stored at -80°C. Total RNA was extracted in heart, brain and liver, and the relative expressions of amp-k, mitCO3, PGC-1α and sirt-1 genes were determined.

Results Kaplan-Meier survival curves showed that controls had a mean survival time of 22.6±4.5hr and ALM animals 72±0hr (p<0.05). Death in controls was accompanied by ~7-fold increase in lactate, while ALM animals maintained lactates similar to baseline over 72hrs. The relative expression of amp-k, PGC-1α, and sirt-1 in heart and brain was 1.5- and 2.7-fold higher in the ALM group compared to controls (p<0.05), with the exception of mtCO3 in heart, which was 19-fold higher. In contrast, amp-k, sirt-1 and mitCO3 gene expression in liver was significantly 29-41% lower in the ALM group compared to controls, and PGC-1α was 75% lower.

Conclusions Small-volume ALM therapy led to 3.3-times longer survival time compared to saline controls after hemorrhagic shock. A hallmark of the ALM-survival phenotype in heart and brain was an upregulation of amp-k, PGC-1α, sirt-1 and mitCO3 to presumably ‘boost’ mitochondrial function and ATP production, and a contrasting downregulation in liver. These central-peripheral differences in gene expression require further investigation.

Level of Evidence Randomized animal study

© 2019 Lippincott Williams & Wilkins, Inc.