Page 133 - JSOM Fall 2020

resuscitation, shed blood was returned with 10mL 0.9% NaCl index. 40,41 Notwithstanding these discrepancies, the results of
AL bolus and whole body O consumption fell by ~15%, sys- How and colleagues reinforce the importance of performing
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temic vascular resistance increased by 30%, and urine out- dose safety studies of ALM therapy in small and large animals
put increased 3-fold in the ALM group compared with saline prior to human translation, which are currently under way at
controls. In our third study, we showed that ALM infusion our institution.
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significantly reduced the inflammatory response in the pig
model of lipopolysaccharide (LPS)-induced endotoxemia. Experimental Conundrum: Why Do Pigs Require
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ALM infusion dropped the MAP to 47mmHg yet maintained
CO and SV leading to no change in tissue oxygen perfusion, Higher ALM Doses Than Rat Models?
with a concomitant fall in whole body oxygen consumption In rats, the resuscitation bolus is 0.7mL/kg and the drip
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(Table 3). 0.5mL/kg/hr, whereas in pigs the optimal bolus is 4mL/kg
and followed by a 3mL/kg/hr infusion. Why is there a species
Our most recent USSOCOM-funded pig study was a mili- difference? A possible explanation is differences in concen-
tary-relevant, noncompressible hemorrhage model induced trations of plasma α-acid glycoprotein (AGP), a major drug
by laparoscopic liver resection. ALM-treated pigs had binding protein, which is >7-fold higher in pigs than rats 42,43
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higher survival (100%) compared with saline controls (80%), (Table 4). AGP, which is also known as orosomucoid, is one
lower HRs and a stable permissive hypotensive state (MAP of the most highly glycosylated proteins in plasma and can
47–61mmHg). At these hypotensive blood pressures, ALM bind >300 drugs including heparin, steroids, histamine. and
was neuroprotective with little or no change in brain lactate lidocaine (70% bound) with higher specificity than albumin
or glycerol compared with 2-fold higher levels in saline con- (>95%). 44,45 Thus, a higher plasma AGP level will influence the
trols (P < .05). We also found a significant 40% reduction free plasma concentrations of lidocaine, which may explain
of hypoxia inducible factor (HIF) expression in ALM-treated why higher ALM doses are required in pigs during resuscita-
brain cortex. These data indicate the ALM therapy resus- tion and stabilization (see earlier). This is further complicated
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citates the animal into a permissive hypotensive range, and during trauma because AGP levels can increase by 2- to 5-fold
reduces secondary brain ischemia at these low MAPs, which is as part of the acute phase response, which would also reduce
consistent with our previous TBI rat study (Table 2). During the bioavailability of lidocaine during infusions. Interestingly,
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infusion of 0.9% NaCl ALM, O delivery was improved from AGP levels in human plasma are lower than pigs, which sug-
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a higher CO and a more compliant vascular system compared gests that the lower bolus and infusion doses in rats may be
with saline controls. In summary, ALM supported a high flow, suitable for translation (Table 4). In addition to bioavailability,
hypotensive, vasodilatory state with improved O delivery and other reasons for rat-to-pig differences may relate to differ-
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cerebral protection in a pig model of noncompressible hepatic ences in drug metabolism and clearance of the drug actives.
hemorrhage (Table 3). Further studies are required to examine this question.
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Pig ALM Resuscitation Controversy: Safety and Translation to Humans
Superior or Inferior?
Understanding the mechanisms of ALM or any drug therapy is
Our three pig studies involving pressure-controlled (~74% vitally important for safe field transition and wider adoption
blood loss) and noncompressible hemorrhage (~30–40% into civilian prehospital medical care because “among 222
blood loss) models are in contrast to the recent study of How novel therapeutics approved by the FDA from 2001 through
and colleagues from Naval Medical Research Unit San Anto- 2010, 71 (32.0%) were affected by a postmarket safety
nio (NAMRU-SA). The group evaluated three different bolus event.” This is an extraordinary statement despite the high
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ALM doses and two drip doses across four treatment groups level of institutional review board scrutiny and FDA oversight
in a pressure-controlled porcine model of hemorrhagic shock on new trials testing new drugs and appropriate pathways
designed to mimic field and Tactical Combat Casualty Care for regulatory approvals. Our mission, therefore, is to avoid
(TCCC) conditions. They reported that ALM was inferior potential adverse events during translation of ALM therapy
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to Hextend in terms of survival but demonstrated a superior through research by further examining the drug’s underlying
coagulation benefit (Table 3). mechanisms and human testing in a “controlled” environment
of major surgery before undertaking more complex trauma
It is difficult at this time to identify the reasons for the loss of trials.
ALM protection although the group did report to us problems
with ALM solubility and “cloudy” solutions (not noted in their Final Remarks
publication). We consider this a “red flag” as we have never
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experienced this problem in our rat or pig studies at James We have presented a brief history of ALM drug development
Cook University, Australia, nor at Aarhus University Hospital, from cardiac surgery to combat casualty care. The potential
Denmark. This implies that one or more of the actives in the military benefit of the IV or IO fluid is that it resuscitates af-
ALM drip solution has exceeded their solubility limits, known ter severe hemorrhage or neurotrauma by improving CNS–
as phase joining or precipitation. It is therefore possible that cardiovascular–endothelium coupling and tissue oxygenation,
increased mortality reported by How and colleagues may have and reduces complications arising from secondary injury pro-
been due to incorrect dosing. In addition, the use of the opi- gression such as coagulopathy, inflammation, and infection.
oid analgesic buprenorphine in their study may also be prob- This conceptual scheme has been termed SHOT. 28,47 The ALM
lematic, as we have shown its combination with ALM leads therapy also has the advantage of having low cube weight and
to less protection and increased mortality. Buprenorphine is is stable over a wide temperature range tailored for small expe-
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known to cause cardiac and respiratory depression including ditionary missions in remote austere environments. The ALM
decreases in systolic and diastolic pressures, MAP, and cardiac fluid IV or IO “drip” may also support and amplify the far

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