Severe traumatic injuries cause 4.4 million deaths globally each year, with haemorrhage responsible for 35–40% of these deaths, making it the second leading cause after brain injuries. Haemorrhagic deaths occur rapidly, often before hospital arrival, necessitating fast, pre-hospital interventions like haemostatic dressings, tourniquets, hypothermia control, tranexamic acid, calcium management, and blood transfusions — an approach known as damage control. However, time to hospital remains a critical factor in survival.
To improve outcomes, researchers are exploring adjuvant treatments that support existing strategies. Current studies focus on enhancing blood products, addressing coagulopathy and inflammation, and improving cell survival during haemorrhagic shock-induced hypoxia.
A recent review highlights potential therapeutic molecules aimed at helping cells withstand low-oxygen conditions during early trauma resuscitation. The authors identify potential drug therapies for haemorrhagic shock (HS), focusing on treatments that promote cell survival during tissue hypoxia and could be used in pre-hospital care.
Six promising molecules were identified based on preclinical evidence of improved survival in animal models: niacin, thiazolidinediones, prolyl hydroxylase domain inhibitors (PHDis), O-GlcNAcylation, valproic acid (VPA), and adenosine–lidocaine–magnesium (ALM) solution.
Niacin
Niacin is a precursor for the production of nicotinamide adenine dinucleotide (NAD) and its reduced form NADH, both of which are essential for numerous redox reactions, including mitochondrial oxidative phosphorylation and glycolysis. NAD levels decrease during HS, suggesting that niacin or its derivatives could improve survival.
Niacin is commonly used to prevent pellagra and has a well-established safety profile with minimal side effects (e.g., itching). It is inexpensive and readily available, which makes it a promising candidate for clinical trials. However, toxicity studies are still required before initiating clinical trials, as doses used in animal studies differ from those used for human vitamin supplementation.
Thiazolidinediones (Glitazones)
Thiazolidinediones bind to peroxisome proliferator-activated receptor gamma (PPAR-γ), a transcription factor involved in inflammatory processes and mitochondrial biogenesis, primarily through PPAR-γ co-activator 1 alpha (PGC1α). Given their effect on mitochondrial function, these compounds have been explored for their potential to enhance cell survival during HS.
Thiazolidinediones, such as rosiglitazone and pioglitazone, are approved for treating type 2 diabetes by increasing insulin sensitivity and are well-tolerated. Although promising in preclinical HS models, there are currently no clinical trials involving thiazolidinediones in HS, though their established safety profile could facilitate future studies.
Prolyl Hydroxylase Domain Inhibitors (PHDis)
PHDis work by increasing levels of hypoxia-inducible factors (HIFs), which are transcription factors that help cells adapt to hypoxic stress by modulating their response to low oxygen. HIF-α is usually degraded in normoxic conditions by prolyl hydroxylase, but PHDis inhibit this enzyme, leading to higher HIF-α levels. These inhibitors also influence carbohydrate metabolism by promoting lactate clearance through the Cori cycle, suggesting they could be beneficial in managing cellular hypoxia, especially in HS.
PHDis were originally developed to treat anaemia in chronic renal failure and chemotherapy-induced anaemia by stimulating erythropoietin secretion. While effective for this purpose, concerns about long-term adverse effects limit their clinical use. They have not yet been tested in clinical trials for HS, and no parenteral formulations are currently available, which could hinder their use in severe trauma treatment. PHDis also hold promise for enhancing lactate clearance, including in cases of lactic acidosis, though no clinical trials have been conducted for this indication either.
O-GlcNAcylation
O-GlcNAcylation is a post-translational modification where a sugar molecule (β-d-N-acetylglucosamine, GlcNAc) is added to proteins, particularly at serine and threonine residues. This process, regulated by OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase), acts as a metabolic sensor, with O-GlcNAc levels reflecting cellular metabolic status. O-GlcNAcylation plays a critical role in cellular stress responses and survival, protecting cells during various stressors such as hypoxia, thermal stress, and chemical exposure. It has also been shown to have a protective effect in sepsis, particularly for cardiac function.
Glucosamine, used in the treatment of osteoarthritis, is generally well tolerated, even at high doses (30–300 mg/kg), which are higher than those used in clinical practice. Clinical trials with glucosamine at these higher doses could pave the way for its use in trauma care. OGA inhibitors, which increase O-GlcNAcylation levels by inhibiting the enzyme responsible for removing GlcNAc, are currently being tested in humans for neurodegenerative diseases such as tauopathies. The development of these inhibitors, such as MK-8719 and LY3372689, holds promise for future clinical trials in severe trauma and HS treatment.
Histone Deacetylase Inhibitors (HDACi)
Histones are proteins around which DNA wraps to form chromatin. Acetylation of histones relaxes chromatin structure, making DNA more accessible for transcription. In contrast, hypoacetylation condenses chromatin, impeding gene expression. Histone deacetylases (HDACs) mediate hypoacetylation, which is implicated in cellular processes during HS. HDAC inhibitors counteract this effect by facilitating transcription dynamics, promoting cell survival. There are 18 isoforms of HDACs in humans, with different functions in various tissues. Some inhibitors are nonspecific, while others target specific HDAC classes.
Valproic acid (VPA), commonly used for epilepsy and migraine prevention, is the most likely HDAC inhibitor to be tested for HS in humans. In animal models, doses of at least 250 mg/kg are necessary for a clinically relevant effect. However, lower doses may suffice in humans. VPA has demonstrated good tolerance in healthy volunteers at 140 mg/kg. Clinical trials in patients with shock are not yet underway, though a trial in the UK is evaluating VPA's effects in protecting the heart and kidneys during cardiac surgery. Further studies are needed to determine the optimal dosing and pharmacodynamics of VPA in trauma patients.
Adenosine–Lidocaine–Magnesium (ALM) Solution
The ALM solution was originally developed for cardiac surgery as a protective solution during cardioplegia, combining adenosine, lidocaine, and magnesium. Adenosine inhibits the sinus node, lidocaine reduces action potential amplitudes by blocking sodium channels, and magnesium stabilises the cardiomyocyte membrane. These effects have prompted investigations into the use of ALM solution in traumatic HS, where the required doses of the three drugs are much lower than their typical individual doses, suggesting a potentiating effect. Despite the short half-lives of the components, the effects of ALM solution last for several hours in animal models.
While initially developed for cardiac surgery, ALM solution has shown promise for treating HS due to its favourable effects on myocardial protection and resuscitation times post-surgery. Each of its components is already authorised for human use, and its affordability and success in cardiac surgery suggest its potential for clinical trials in trauma settings. However, no such trials are currently underway, partly due to the incomplete understanding of its mechanisms in the context of shock.
While these molecules show promise, most of the research has been conducted in animal models. More work is needed to confirm these results in humans, as changes in biological models may not always replicate initial findings.
Several molecules presented, such as niacin, glitazones, glucosamine, and VPA, are already approved for other human indications, making them suitable candidates for "drug repurposing." However, Phase 1 clinical trials are necessary to determine their safety and efficacy in trauma patients. The drugs may behave differently in severely traumatised patients due to altered absorption, renal and hepatic clearance, and enzyme function under conditions like hypothermia.
Source: Critical Care
Image Credit: iStock
