Page 131 - JSOM Fall 2020

ALM for Trauma: Teaching Old Drugs New Tricks by up to 60% and acted like a pharmacological tourniquet.
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We argued that this may be related to ALM correction of co-
Our first proof-of-concept ALM trauma experiments were agulopathy, which was also consistent with preserved platelet
conducted in 2009. 16,17 We have subsequently shown in rat function and reduced endothelial activation and suppressed
models that boluses and infusions of low-dose ALM protect systemic inflammation (Tables 1 and 2). In addition to trau-
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the heart and whole body against regional myocardial isch- matic hemorrhage, we also examined the effect of the same 3%
emia, 18–20 cardiac arrest, 21,22 pressure- and volume-controlled NaCl ALM bolus and 0.9% NaCl ALM drip therapy in a rat
hemorrhagic shock, 16,17,23 polymicrobial sepsis, 24,25 and surgi- model of moderate traumatic brain injury (TBI) and showed
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cal trauma. Importantly, the individual actives, A, L, or M do a survival benefit compared with controls, and a major re-
not confer these benefits alone. 10,27 Standout features of ALM duction in secondary injury expression including correction of
protection and pro-survival properties include (1) potent anti- coagulopathy, blunting of endothelial activation, and reduced
arrhythmic, (2) lowering myocardial energy demand, (3) abil- systemic inflammation and brain injury markers (Table 2).
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ity to hypotensively resuscitate mean arterial pressure (MAP)
from different shock states, (4) correction of coagulopathy, (5) The second noncompressible hemorrhage study in rats exam-
preservation of platelets, 6) endothelial protection, (7) anti- ined if ALM therapy could increase survival to 72 hours in
inflammatory, and (8) immunomodulatory 10,28 (Table 1). Stud- the conscious animal. We showed the mean survival time for
ies carried out by US Army Institute of Surgical Research have saline controls was 22 hours and ALM group was 72 hours
also shown that ALM protects against endothelial glycocalyx (P < .001, experimental endpoint). Survival was associated
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shedding with 97% restoration after hemorrhagic shock. On with higher CO, reduced inflammation, protection from im-
the basis of our ALM trauma studies, which are summarized munosuppression, preserved platelet function, correction of
next, we hypothesize that if the central nervous system (CNS) coagulopathy, and differential regulation of the master genes
control of cardiovascular coupling is maintained following of metabolism. Expression of ampk, sirt-1, and PGC-1α were
trauma, the endothelium will be protected, mitochondrial en- significantly upregulated 2- to 3-fold, and mtCO was upreg-
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ergetics will be maintained, and coagulopathy and inflamma- ulated 10-fold in the heart and brain compared with controls.
tion will be minimized. This conceptual scheme is termed the The upregulation of mtCO3 indicates improved structure and
Systems Hypothesis of Trauma (SHOT) and helps to explain stability of cytochrome c oxidase, the complex that drives ATP
why certain groups of severely bleeding trauma patients are synthesis. More recently, we have shown TFAM (transcrip-
still dying despite receiving the best medical care. 28
tion factor A, mitochondrial), a gene involved in mitochon-
drial biogenesis, was also significantly increased in heart and
TABLE 1 Defining the ALM-Induced Survival Phenotype After brain. Mitochondrial biogenesis is the process by which cells
Severe Trauma increase mass via growth and division of preexisting mito-
• Potent antiarrhythmic chondrial networks. In direct contrast, ALM downregulated
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• Cardiac preconditioning mimetic and lowers energy demand ampk, sirt-1, PGC-1α, and mtCO expression in the periphery.
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• Correction of trauma-induced coagulopathy For example, mtCo3 expression in liver was downregulated
• Preserved platelet aggregation by 90% indicating a major reduction of hepatic ATP demand.
• Reduced systemic inflammation Our new data appear to show that ALM switches and repro-
• Protection against immunodeficiency and infection grams the whole body into a pro-survival phenotype with sup-
pression of secondary injury processes. Key questions remain:
• Improved left ventricular–arterial coupling Given that the half-lives of each active in ALM are seconds to
• Increased blood flow to brain and gut a few hours, when does the “switch” occur? How long can
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• Restoration of endothelial–glycocalyx shedding the survival phenotype be sustained? Future efforts will exam-
• Improved tissue oxygenation ine if survival time can extend to 7 days which has significant
• Hypotensive resuscitation with neuroprotection military relevance.
• Reduced sympathetic/parasympathetic input to heart
• Maintenance of membrane potential in healthy and injured cells Rat-to-Pig Translation
• Differential expression of master genes of metabolism
• Improved thermoregulatory control In our first translational study in pigs, we showed that a 20mL
bolus of 7.5% NaCl ALM (0.5mL/kg) led to a 40% reduction
• Improved central nervous system–cardiovascular–endothelial in fluid volume (IV Ringers acetate) required to increase MAP
coupling as part of the Systems Hypothesis of Trauma (SHOT)
from 30–35mmHg to a target MAP of 50mmHg after 90 min
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Noncompressible Hemorrhagic Shock of 74% controlled blood loss. We also found returning shed
blood (1.6 to 2L) after 60 min with a 10mL bolus of 0.9%
Shock is: “a momentary pause in the act of death.” NaCl AL resulted in a significant 27% drop in whole body
—John Collins Warren (1895) O consumption, higher CO, and significantly improved renal
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function compared with controls 10,35 (Table 3). In our second
In 2015 our first USSOCOM-funded study showed that 3% study using the pressure-controlled hemorrhage model (73%
NaCl ALM bolus and 0.9% NaCl ALM drip improved sur- blood loss), a single bolus of 4mL/kg 7.5% NaCl ALM bolus
vival (100% vs 62% for controls), significantly increased (~7% of shed volume), with no other fluid, raised MAP from
cardiac output (CO) (2.4-fold) and left ventricular fractional 30–35 to 55mmHg accompanying a nearly 2-fold increase in
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shortening, and increased blood flow to gut and kidney. This stroke volume (SV) at 60 min compared with saline controls,
acute experiment in anesthetized rats involved uncontrolled which began to decompensate (MAP 32 ± 3mmHg) with one
blood loss from resecting the liver (60% left lateral lobe and death. The 2-fold increase in SV was due to an increase in
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50% medial lobe) with 6-hour monitoring. An unexpected systolic ejection time (129 ± 10 vs 84 ± 12 ms, P < .05) and
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finding was showing that ALM reduced internal blood loss ~20% decrease in heart rate (HR). After 60 min hypotensive
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Development of ALM Fluid Resuscitation Therapy | 129