Novel Treatment ideas for hemorrhagic shock: What the future holds
Myron Yaster MD and Justin L. Lockman MD, MSEd
Today’s Pediatric Anesthesia Article of the Day is a repost from August 29,2022 to prep you for tomorrow’s PAAD. This article is not really a pediatric anesthesia article per se but it covers a topic that is always just below the surface of our consciousness, namely, what is the pathophysiology of (traumatic) hemorrhage and what new therapies are on the horizon or on the cusp of FDA approval. The basic premise: what happens if we don’t have the resources to treat traumatic hemorrhage as might happen in mass casualty scenarios and war (think of Ukraine). As you might expect from a journal published by the American Physiological Society, it is very basic science driven and goes into great detail about what happens to the Krebs cycle, forward and reversed electron transport in shock, and ischemia induced cell death during hemorrhage. Fear not though, it is well worth the effort of reading and discussing this paper amongst yourselves and trainees (it would make a GREAT journal club article). And it is a great basic science article that sets the stage for tomorrow’s PAAD.
But first a word about biochemical pathways from Dr. G:
Original article
Carmen Hinojosa-Laborde, Ian L Hudson, Evan Ross, Lusha Xiang, Kathy L Ryan. Pathophysiology of Hemorrhage as It Relates to the Warfighter. Physiology (Bethesda). 2022 May 1;37(3):141-153. PMID: 35001653
The two critical deficits in hemorrhage are (1) the loss of blood itself leading to hemodynamic instability and (2) a decrease in oxygen/substrate delivery to vital organs - shock. Thus, the most effective treatment is fluid resuscitation to increase intravascular volume, thereby restoring blood pressure, and the optimal resuscitation fluid would also have the ability to carry oxygen as well as stop ongoing bleeding. Fresh whole blood then, is the obvious best resuscitative fluid – replacing the deficit with the same concentration of clotting factors, platelets, etc. as are being lost. Unfortunately, we have been in a blood shortage for eternity and fresh whole blood is usually unavailable. In this setting, Massive Transfusion Protocols (MTP) attempt to reconstitute whole blood by using packed red blood cells, fresh frozen plasma, and platelets in fixed ratios (precise ratios differ by center, but usually 1:1:1). Obviously, in combat and even in the ORs, refrigerated/frozen products and other logistics may not make this possible; delay may accelerate hypoxic/ischemic injury, and hypothermia may worsen bleeding due to coagulopathy. To this end, “new pharmacological adjuncts are being considered that will further improve oxygen delivery and utilization, stabilize mitochondrial function, and/or prevent regulated cell death (RCD)”. 1
Artificial blood substitutes such as hemoglobin-based oxygen carriers make a lot of sense in theory. Unfortunately, none are currently FDA approved. Plasma, which contains clotting factors and is protective of endothelial function, has historically presented logistical challenges of storage, freezing and thawing. Not any more, apparently! “Freeze-dried (lyophilized) plasma doesn’t have these problems and has efficacy and physiological responses equivalent to thawed plasma. Because of this, freeze dried plasma is currently in use by the US and other militaries” and will probably be carried by civilian ambulances in the near future.1
What if we could give patients a transfusion of their own blood, moving it from where it’s not needed to where it is? From the article: “Another approach to maintain blood pressure is to pharmacologically produce vasoconstriction. Although general vasoconstriction with norepinephrine is counterproductive, recent studies suggest that selective venoconstriction may be helpful. Centhaquine, a promising resuscitative agent, acts by stimulating alpha2b-adrenergic receptors in the veins to cause constriction, which results in an increase in venous return, cardiac output, and mean arterial pressure in animal models of hemorrhage.2,3 It has also been found to prevent AKI and restore renal blood flow in a rat hemorrhage model.4 Centhaquine has completed phase III clinical trials in hypovolemic shock patients and has been demonstrated to increase pulse pressure, reduce blood lactate levels, and improve base deficit associated with a reduction in multiple organ dysfunction and 28-day all-cause mortality”.1
What if we could get the same amount of hemoglobin to drop off more oxygen at ischemic sites? Another strategy discussed is to “facilitate oxygen diffusion into tissues to maintain tissue oxygenation under ischemic conditions. The rate of oxygen diffusion from red blood cells into surrounding tissues is determined by the pressure gradient of oxygen and the resistance to oxygen transport, with plasma providing a great deal of this resistance. Trans-sodium crocetinate 5 is an oxygen diffusion-enhancing compound that increases hydrogen bonding among water molecules, thus enhancing the rate and distance of oxygen diffusion into tissues”.1 Could it be used in hemorrhagic shock? Are there unanticipated effects? Trials are already underway!
One of the consequences of shock and ischemia is the development of reactive oxygen species (ROS) that are detrimental during both the period of ischemia AND during reperfusion and reoxygenation. Drugs targeting ROS may impact cellular responses to hypoxia and reoxygenation. Will they work? At this moment no one knows and these are only theoretical treatment options, but keep an eye out for them. Finally, regulated cell death may be therapeutic targets as well. Drugs like valproic acid and cyclosporin A act to stabilize mitochondria after ischemia. Whether or not they work under the ischemic conditions following hemorrhage is unclear, but they are also targets for future investigations.
The authors conclude: “Undoubtedly, there is no one “silver bullet,” but ultimate resuscitation strategies will require combinations of oxygen-delivering solutions to increase blood volume and adjuncts to make the host tissue more tolerant to ischemia.”1 While these treatments are still years away and perhaps even further away in children, we look forward to a future when hemorrhagic trauma deaths (accidental or surgical) are far less common than today. What do you think?
References
1. Hinojosa-Laborde C, Hudson IL, Ross E, Xiang L, Ryan KL: Pathophysiology of Hemorrhage as It Relates to the Warfighter. Physiology (Bethesda) 2022; 37: 141-153
2. Lavhale MS, Havalad S, Gulati A: Resuscitative effect of centhaquin after hemorrhagic shock in rats. J Surg Res 2013; 179: 115-24
3. Gulati A, Choudhuri R, Gupta A, Singh S, Ali SKN, Sidhu GK, Haque PD, Rahate P, Bothra AR, Singh GP, Maheshwari S, Jeswani D, Haveri S, Agarwal A, Agrawal NR: A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin(®)) as a Resuscitative Agent in Hypovolemic Shock Patients. Drugs 2021; 81: 1079-1100
4. Ranjan AK, Zhang Z, Briyal S, Gulati A: Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia. Front Pharmacol 2021; 12: 616253
5. Stennett AK, Murray RJ, Roy JW, Gainer JL: Trans-sodium crocetinate and hemorrhagic shock. Shock 2007; 28: 339-44