Background and Objectives: Traumatic hemorrhage is a leading cause of death. Our aim was to examine the effect of adenosine, lidocaine and magnesium (ALM) resuscitation therapy with and without fresh frozen plasma (FFP) or fresh whole blood (FWB) in a rat model of non-compressible hemorrhage. Materials and Methods: Anesthetized adult male Sprague-Dawley rats (439 ± 46 g) randomly assigned to (1) Shams (surgical trauma and liver isolation only without hemorrhage) (n = 34), (2) Saline controls (n = 34), or (3) ALM therapy (n = 34), underwent liver resection and uncontrolled bleeding. After 5 h 3% NaCl ± ALM bolus and 0.9% NaCl ± ALM drip fluid resuscitation, each group was randomized to receive no transfusion (NT) (n = 10 per treatment group), FFP (n = 12), or FWB (n = 12), and monitored for 72 h. Survival, hemodynamics, lactate, hematology, coagulation, platelet function, and lung histopathology were measured. Results: Sham, Saline and ALM NT survival were 50%, 0% and 100%. Sham survival increased to 75% with FFP, but not FWB (50%), and only marginally in the Saline group (8% and 17%, respectively). ALM protection was lost after 1–2 days with FFP and FWB (8% and 0% survival). Mortality was associated with acute lung injury, inflammation, activation of innate immunity, intrinsic hypocoagulopathy, and metabolic acidosis. Survival was associated with maintained platelet count and aggregation. Acute phase protein fibrinogen increased ~2.5 times in both survivors and non-survivors. Conclusions: ALM therapy without FFP or FWB transfusion significantly improved survival, reduced lung injury, preserved platelet function, and decreased immune and metabolic dysfunction. Blood products administered 5 h after injury did not significantly improve survival after non-compressible hemorrhage. Surgical trauma (laparotomy and liver isolation) also contributed to poor outcomes. The trauma and transfusion-related multi-system failure requires further investigation.

Traumatic brain injuries (TBIs) with increased intracranial pressure (ICP) require time-sensitive surgical intervention. In non-metropolitan areas, neurosurgeons are often unavailable to provide definitive treatment. Therapeutic surgical intervention by a non-neurosurgeon, for example, general surgeons, is a potential alternative; however, the feasibility and utility of non-specialist intervention are poorly defined within the literature. A scoping review was conducted within Scopus, Emcare, MEDLINE and CINAHL for original literature about emergency neurosurgical interventions performed by a non-neurosurgeon for TBIs in non-metropolitan settings without prompt access to a neurosurgeon. This search yielded 20 studies that included over 2000 surgical interventions in 13 countries. General surgeons most commonly performed the procedures on patients with computed tomography (CT)-confirmed lesions. Mortality rates were heterogeneous, ranging from 0% to 67% in small cohorts with variable follow-up periods. Mortality was consistently higher in patients with subdural haematomas (SDHs) opposed to extradural haematomas (EDHs). Morbidity was measured in 13 studies, commonly via the Glasgow outcome scale (GOS). Most studies had access to remote neurosurgical advice via telehealth. Overall, these 20 studies provided incomplete information regarding mortality rates and functional outcomes from this alternative practise. The present study concludes that emergency decompression by a non-neurosurgeon for patients with severe TBIs may be lifesaving for patients without timely access to a neurosurgical centre. Our study further highlights the need for further research, training and resource allocation, including strengthening telecommunication pathways, to support patient access to lifesaving neurosurgical interventions in these environments, and ultimately address surgical inequalities in rural and remote regions of the world.

BACKGROUND:The timing for anterior cruciate ligament (ACL) reconstruction (ACLR) and strategies to enhance postoperative healing remain controversial, with little known regarding potential sex-specific differences. Perioperative adenosine, lidocaine, and Mg2+ (ALM) therapy has been shown to promote joint tissue healing in an experimental model of early ACLR; however, an early-late comparison of ALM's effects on postoperative recovery remains to be investigated. PURPOSE:To examine the effect of delayed surgery in males and females, and the effect of ALM therapy to augment joint tissue healing. STUDY DESIGN:Controlled laboratory study. METHODS:After noninvasive ACL rupture, adult male (n = 38) and female (n = 39) Sprague-Dawley rats were randomly divided into early (3-day delay) or delayed (14-day delay) ACLR surgery groups, and to receive ALM therapy or saline. During ACLR, an ALM or saline intravenous 1-hour infusion was commenced before first incision, and an intra-articular bolus of ALM or saline was administered at surgery end. Animals were monitored to 28 days postoperatively, and pain, functional recovery, inflammation and joint tissue repair markers, and histopathology were assessed. RESULTS:In the first postoperative week, delayed ACLR was associated with a lymphocyte-driven immune response, with less systemic inflammation compared with early ACLR. This response was associated with faster recovery of body weight, and less joint pain and swelling in both sexes. At 28 days postoperatively, graft and adjacent joint tissue healing appeared more advanced in females than males, regardless of surgical timing. In both sexes, ALM blunted synovial levels of inflammatory mediators (tumor necrosis factor-α and interleukin-1β), reduced injury markers in articular cartilage, and improved graft healing, evidenced from increased expression of tissue repair markers and bony ingrowth at the graft-tunnel interface. CONCLUSION:Delayed versus early ACLR improves joint recovery, and ALM further augments healing by blunting the early immunoinflammatory response in both sexes, irrespective of surgical timing. CLINICAL RELEVANCE:Delaying ACLR has the advantage of reducing the pre- and postoperative joint inflammatory environment, with improved outcomes. Perioperative ALM therapy may augment joint healing in both sexes after ACLR.

Improvements have been made in optimizing initial care of trauma patients, both in prehospital systems as well as in the emergency department, and these have also favorably affected longer term outcomes. However, as specific treatments for bleeding are largely lacking, many patients continue to die from hemorrhage. Also, major knowledge gaps remain on the impact of tissue injury on the host immune and coagulation response, which hampers the development of interventions to treat or prevent organ failure, thrombosis, infections or other complications of trauma. Thereby, trauma remains a challenge for intensivists. This review describes the most pressing research questions in trauma, as well as new approaches to trauma research, with the aim to bring improved therapies to the bedside within the twenty-first century.

Spontaneous regression (SR) of chronic lymphocytic leukemia (CLL) is a rare event (0.2% - 1%). Some advances have been made in understanding the tumor genetic characteristics of such patients, although the immunological mechanisms leading to SR remain unclear. We describe a series of immunological events related to regression dynamics, allowing the identification of a SR phase (associated with >99% reduction of CLL cells in peripheral blood and adenopathy resolution in less than one year, concurrently with a nine-fold increase in monocyte counts, high B2M and the appearance of an oligoclonal serum IgG band), followed by a persistent regression (PR) phase that was maintained for ≥17 months. Our observations highlight a role of monocytes and B2M in SR, potentially related to immune activation. The oligoclonal IgG band detected during SR was maintained in PR, suggesting either a change in the ability of malignant cells (IgM+IgD+IgG‒) to differentiate into IgG-secreting cells, or an anti-tumor humoral response from normal B cells. These findings imply immune and molecular mechanisms required to eliminate malignant cells and might suggest new immunotherapies for CLL.

Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems' perspective and future opportunities. We argue that targeting the body's early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O2 supply. Future research will investigate the potential translation to humans.

AimsAdenosine, lidocaine, and Mg2+ (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery.MethodsMale (n = 21) and female (n = 21) adult Sprague-Dawley rats were randomly divided into ALM or Saline control treatment groups. Three days after ACL rupture, animals underwent ACLR. An ALM or saline intravenous infusion was commenced prior to skin incision, and continued for one hour. An intra-articular bolus of ALM or saline was also administered prior to skin closure. Animals were monitored to 28 days, and joint function, pain, inflammatory markers, histopathology, and tissue repair markers were assessed.ResultsDespite comparable knee function, ALM-treated males had reduced systemic inflammation, synovial fluid angiogenic and pro-inflammatory mediators, synovitis, and fat pad fibrotic changes, compared to controls. Within the ACL graft, ALM-treated males had increased expression of tissue repair markers, decreased inflammation, increased collagen organization, and improved graft-bone healing. In contrast to males, females had no evidence of persistent systemic inflammation. Compared to controls, ALM-treated females had improved knee extension, gait biomechanics, and elevated synovial macrophage inflammatory protein-1 alpha (MIP-1α). Within the ACL graft, ALM-treated females had decreased inflammation, increased collagen organization, and improved graft-bone healing. In articular cartilage of ALM-treated animals, matrix metalloproteinase (MMP)-13 expression was blunted in males, while in females repair markers were increased.ConclusionAt 28 days, ALM therapy reduces inflammation, augments tissue repair patterns, and improves joint function in a sex-specific manner. The study supports transition to human safety trials.Cite this article: Bone Joint Res 2024;13(6):279–293.

Severe burn injury elicits a profound stress response with the potential for high morbidity and mortality. If polytrauma is present, patient outcomes appear to be worse. Sex-based comparisons indicate females have worse outcomes than males. There are few effective drug therapies to treat burn shock and secondary injury progression. The lack of effective drugs appears to arise from the current treat-as-you-go approach rather than a more integrated systems approach. In this review, we present a brief history of burns research and discuss its pathophysiology from a systems' perspective. The severe burn injury phenotype appears to develop from a rapid and relentless barrage of damage-associated molecular patterns, pathogen-associated molecular patterns, and neural afferent signals, which leads to a state of hyperinflammation, immune dysfunction, coagulopathy, hypermetabolism, and intense pain. We propose that if the central nervous system control of cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored early, these secondary injury processes may be minimized. The therapeutic goal is to switch the injury phenotype to a healing phenotype by reducing fluid leak and maintaining tissue O2 perfusion. Currently, no systems-based therapies exist to treat severe burns. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine, and magnesium (ALM) to treat hemorrhagic shock, traumatic brain injury, and sepsis. Our early studies indicate that the ALM therapy holds some promise in supporting cardiovascular and pulmonary functions following severe burns. Future research will investigate the ability of ALM therapy to treat severe burns with polytrauma and sex disparities, and potential translation to humans.

The management of severe burns remains a complex challenge. Adenosine, lidocaine, and magnesium (ALM) resuscitation therapy has been shown to protect against hemorrhagic shock and traumatic injury. The aim of the present study was to investigate the early protective effects of small-volume ALM fluid resuscitation in a rat model of 30% total body surface area (TBSA) thermal injury. Male Sprague-Dawley rats (320-340 g; n = 25) were randomly assigned to: 1) Sham (surgical instrumentation and saline infusion, without burn, n = 5), 2) Saline resuscitation group (n = 10), or 3) ALM resuscitation group (n = 10). Treatments were initiated 15-min after burn trauma, including 0.7 mL/kg 3% NaCl ± ALM bolus and 0.25-0.5 mL/kg/h 0.9% NaCl ± ALM drip, with animals monitored to 8.25-hr post-burn. Hemodynamics, cardiac function, blood chemistry, hematology, endothelial injury markers and histopathology were assessed. Survival was 100% for Shams and 90% for both ALM and Saline groups. Shams underwent significant physiological, immune and hematological changes over time as a result of surgical traums. ALM significantly reduced malondialdehyde levels in the lungs compared to Saline (P = .023), and showed minimal alveolar destruction and inflammatory cell infiltration (P < .001). ALM also improved cardiac function and oxygen delivery (21%, P = .418 vs Saline), reduced gut injury (P < .001 vs Saline), and increased plasma adiponectin (P < .001 vs baseline). Circulating levels of the acute phase protein alpha 1-acid glycoprotein (AGP) increased 1.6-times (P < .001), which may have impacted ALM's therapeutic efficacy. We conclude that small-volume ALM therapy significantly reduced lung oxidative stress and preserved alveolar integrity following severe burn trauma. Further studies are required to assess higher ALM doses with longer monitoring periods.

Adenosine, lidocaine and Mg2+ (ALM) solution is an emerging therapy that reduces secondary injury after intravenous administration in experimental models of traumatic brain injury (TBI). Intranasal delivery of ALM may offer an alternative route for rapid, point-of-care management of TBI. As a preliminary safety screen, we evaluated whether ALM exerts cytotoxic or inflammatory effects on primary human nasal epithelial cells (pHNEC) in vitro. Submerged monolayers and air-liquid interface cultures of pHNEC were exposed to media only, normal saline only, therapeutic ALM or supratherapeutic ALM for 15 or 60 min. Safety was measured through viability, cytotoxicity, apoptosis, cellular and mitochondrial stress, and inflammatory mediator secretion assays. No differences were found in viability or cytotoxicity in cultures exposed to saline or ALM for up to 60 min, with no evidence of apoptosis after exposure to supratherapeutic ALM concentrations. Despite comparable inflammatory cytokine secretion profiles and mitochondrial activity, cellular stress responses were significantly lower in cultures exposed to ALM than saline. In summary, data show ALM therapy has neither adverse toxic nor inflammatory effects on human nasal epithelial cells, setting the stage for in vivo toxicity studies and possible clinical translation of intranasal ALM therapy for TBI treatment.

INTRODUCTION:Non-compressible torso hemorrhagic (NCTH) shock is the leading cause of potentially survivable trauma on the battlefield. New hypotensive drug therapies are urgently required to resuscitate and protect the heart and brain following NCTH. Our aim was to examine the strengths and limitations of permissive hypotension and discuss the development of small-volume adenosine, lidocaine, and Mg2+ (ALM) fluid resuscitation in rats and pigs. MATERIALS AND METHODS:For review of permissive hypotension, a literature search was performed from inception up to November 2023 using PubMed, Cochrane, and Embase databases, with inclusion of animal studies, clinical trials and reviews with military and clinical relevance. For the preclinical study, adult female pigs underwent laparoscopic liver resection. After 30 minutes of bleeding, animals were resuscitated with 4 mL/kg 3% NaCl ± ALM bolus followed 60 minutes later with 4 h 3 mL/kg/h 0.9% NaCl ± ALM drip (n = 10 per group), then blood transfusion. Mean arterial pressure (MAP) and cardiac output (CO) were continuously measured via a left ventricular pressure catheter and pulmonary artery catheter, respectively. Systemic vascular resistance (SVR) was calculated using the formula: 80 × (MAP - CVP)/CI. Oxygen delivery was calculated as the product of CO and arterial oxygen content. RESULTS:Targeting a MAP of ∼50 mmHg can be harmful or beneficial, depending on how CO and SVR are regulated. A theoretical example shows that for the same MAP of 50 mmHg, a higher CO and lower SVR can lead to a nearly 2-fold increase in O2 supply. We further show that in animal models of NCTH, 3% NaCl ALM bolus and 0.9% NaCl ALM drip induce a hypotensive, high flow, vasodilatory state with maintained tissue O2 supply and neuroprotection. ALM therapy increases survival by resuscitating the heart, reducing internal bleeding by correcting coagulopathy, and decreasing secondary injury. CONCLUSIONS:In rat and pig models of NCTH, small-volume ALM therapy resuscitates at hypotensive pressures by increasing CO and reducing SVR. This strategy is associated with heart and brain protection and maintained tissue O2 delivery. Translational studies are required to determine reproducibility and optimal component dosing. ALM therapy may find wide utility in prehospital and far-forward military environments.

For decades, left ventricular ejection fraction (LVEF < 35%) has been a mainstay for identifying heart failure (HF) patients most likely to benefit from an implantable cardioverter defibrillator (ICD). However, LVEF is a poor predictor of sudden cardiac death (SCD) and ignores 50% of HF patients with mildly reduced and preserved LVEF. The current international guidelines for primary prophylaxis ICD therapy are inadequate. Instead of LVEF, which is not a good measure of LV contractility or hemodynamic characterization, we hypothesize ventriculo-arterial (VA) coupling combined with fragmented QRS (fQRS) will improve risk stratification and patient suitability for an ICD. Quantifying cardiac and aortic mechanics, and predicting active arrhythmogenic substrate, from varying fQRS morphologies, may help to stratify ischemic and non-ischemic patients with different functional capacities and predisposition for lethal arrhythmias. We propose HF patients with a low physiological reserve may not benefit from ICD therapy, whereas those patients with higher reserves and extensive arrhythmogenic substrate may benefit. Our hypothesis combining VA coupling with fQRS changes has the potential to widen HF patient participation (low and high LVEF) and advance personalized medicine for HF patients at high risk of SCD.

Background and objectives: The main problem of vascular preservation is the maintenance of vessel graft quality and function following extended storage. Conventional preservation solutions such as histidine–tryptophan–ketoglutarate (HTK) solution, Phosphate-Buffer Solution (PBS), or sodium chloride 0.9% has been shown to be inadequate in preserving vascular physiological function after 3 days of cold storage. This study aimed to evaluate whether adenosine and lidocaine (AL) in a modified Krebs–Henseleit (KH) solution can preserve the function and histological structure of rat aortic rings after 6 days. Materials and Methods: Thirty-five aortic rings from male Wistar rats (200–300 g) were harvested and immediately immersed in one of the assigned cold preservation solutions: standard KH, modified KH (mod KH) with lower calcium (Ca2+) and higher magnesium content (Mg2+) with or without adenosine and lidocaine (mod KH-AL), and modified KH with AL, insulin, and melatonin (Mod KH-ALMI). The contraction and relaxation function of the aortic rings were examined using an isometric force transducer after 6 days of cold preservation. Hematoxylin and eosin staining were used to analyze the rings’ histological structure. Results: Vascular contraction and relaxation functions were severely affected after a 6-day cold storage period in standard KH. Modifying the KH solution by reducing the Ca2+ and increasing the Mg2+ levels greatly recovered the vessel functions. The addition of AL or ALMI to the modified KH did not further recover vascular contractility. However, only the addition of AL to the modified KH increased the ACh-induced relaxation at 6 days when compared to the conventional KH, suggesting that endothelium preservation is improved. From histological analysis, it was found that the addition of AL but not ALMI further improved the endothelial lining and the structure of the elastic membrane layers of the preserved vessels after 6 days of cold preservation. Conclusions: The addition of AL to low calcium-high magnesium KH solution significantly enhanced endothelial preservation and improved endothelial-induced relaxation of preserved vessels after 6 days of cold storage.

OBJECTIVE:To identify and describe differences in demographics, injury characteristics, and outcomes between rural and urban patients suffering brain injury. DATA SOURCES:CINAHL, Emcare, MEDLINE, and Scopus. REVIEW METHODS:A systematic review and meta-analysis of studies comparing epidemiology and outcomes of rural and urban brain trauma was conducted in accordance with PRISMA and MOOSE guidelines. RESULTS:36 studies with ~ 2.5-million patients were included. Incidence of brain injury was higher in males, regardless of location. Rates of transport-related brain injuries, particularly involving motorized vehicles other than cars, were significantly higher in rural populations (OR:3.63, 95% CI[1.58,8.35], p = 0.002), whereas urban residents had more fall-induced brain trauma (OR:0.73, 95% CI[0.66,0.81], p < 0.00001). Rural patients were 28% more likely to suffer severe injury, indicated by Glasgow Coma Scale (GCS)≤8 (OR:1.28, 95% CI[1.04,1.58], p = 0.02). There was no difference in mortality (OR:1.09, 95% CI[0.73,1.61], p = 0.067), however, urban patients were twice as likely to be discharged with a good outcome (OR:0.52, 95% CI[0.41,0.67], p < 0.00001). CONCLUSIONS:Rurality is associated with greater severity and poorer outcomes of traumatic brain injury. Transport accidents disproportionally affect those traveling on rural roads. Future research recommendations include addition of prehospital data, adequate follow-up, standardized measures, and sub-group analyses of high-risk groups, e.g. Indigenous populations.

Severe traumatic brain injury (TBI) is a devastating injury with a mortality of ∼ 25-30 %. Despite decades of high-quality research, no drug therapy has reduced mortality. Why is this so? We argue two contributing factors for the lack of effective drug therapies include the use of specific-pathogen free (SPF) animals for translational research and the flawed practice of single-nodal targeting for drug design. A revolution is required to better understand how the whole body responds to TBI, identify new markers of its progression, and discover new system-acting drugs to treat it. In this review, we present a brief history of TBI, discuss its system's pathophysiology and propose a new research strategy for the 21st century. TBI progression develops from injury signals radiating from the primary impact, which can cause local ischemia, hemorrhage, excitotoxicity, cellular depolarization, immune dysfunction, sympathetic hyperactivity, blood-brain barrier breach, coagulopathy and whole-body dysfunction. Metabolic reprograming of immune cells drives neuroinflammation and secondary injury processes. We propose if sympathetic hyperactivity and immune cell activation can be corrected early, cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored, and secondary injury minimized with improved patient outcomes. The therapeutic goal is to switch the injury phenotype to a healing phenotype by restoring homeostasis and maintaining sufficient tissue O2 delivery. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat TBI and have shown that it blunts the CNS-stress response, supports cardiovascular function and reduces secondary injury. Future research will investigate its suitability for human translation.

Background: Head trauma is a leading cause of death and disability worldwide. Young males, Indigenous people, and rural/remote residents have been identified as high-risk populations for head trauma, however, Australian research is limited. Our aim was to define and describe the incidence, demographics, causes, prehospital interventions, and outcomes of head trauma patients transported by aeromedical services within North Queensland, Australia. We hypothesized that young, Indigenous males living remotely would be disproportionately affected by head trauma. Methods: We conducted a retrospective study of all head trauma patients transferred by air to or between Townsville, Cairns, Mount Isa and Mackay Hospitals between January 1, 2016 and December 31, 2018. Patients were identified from the Trauma Care in the Tropics data registry and followed for a median 30-months postinjury. Primary endpoints were patient and injury characteristics. Secondary outcome measures were hospital stay and mortality. Results: A total of 981 patients were included and 31.1 % were Indigenous. Sixty-seven percent of injuries occurred remotely and the median time from injury to hospital was 5.8-hours (range 67-3780 min). Eighty percent of severe head injuries occurred in males (p = 0.007). Indigenous and remote patients were more likely to sustain mild injuries. The most common mechanism of injury overall was vehicle accident (37.5 %), compared to assault in the Indigenous subgroup (46.6 %, p<0.001). The overall mortality rate was 4.9 %, with older age and lower initial Glasgow Coma Score significant predictors of in-hospital mortality. Prehospital intubation was associated with a 7-fold increased risk of mortality (p = 0.056), while patients that received tranexamic acid (TXA) were almost 5-times more likely to die. Conclusions: In North Queensland, young Indigenous males are at highest risk of traumatic head injuries. Vehicle accidents are an important preventable cause of head injury in the region. TXA administration is an important consideration for remote head trauma retrievals, in which time to emergency care is prolonged. Appropriate treatment and risk stratification strategies considering time to definitive care, severity of injury, and other prehospital patient factors require further investigation.

If a trauma (or infection) exceeds the body’s evolutionary design limits, a stress response is activated to quickly restore homeostasis. However, when the injury severity score is high, death is often imminent. The goal of this review is to provide an update on the effect of small-volume adenosine, lidocaine and Mg2+ (ALM) therapy on increasing survival and blunting secondary injury after non-compressible hemorrhagic shock and other trauma and infective/endotoxemic states. Two standout features of ALM therapy are: (1) resuscitation occurs at permissive hypotensive blood pressures (MAPs 50–60 mmHg), and (2) the drug confers neuroprotection at these low pressures. The therapy appears to reset the body’s baroreflex to produce a high-flow, hypotensive, vasodilatory state with maintained tissue O2 delivery. Whole body ALM protection appears to be afforded by NO synthesis-dependent pathways and shifting central nervous system (CNS) control from sympathetic to parasympathetic dominance, resulting in improved cardiovascular function, reduced immune activation and inflammation, correction of coagulopathy, restoration of endothelial glycocalyx, and reduced energy demand and mitochondrial oxidative stress. Recently, independent studies have shown ALM may also be useful for stroke, muscle trauma, and as an adjunct to Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). Ongoing studies have further shown ALM may have utility for burn polytrauma, damage control surgery and orthopedic surgery. Lastly, we discuss the clinical applications of ALM fluid therapy for prehospital and military far-forward use for non-compressible hemorrhage and traumatic brain injury (TBI).

Background Early dysregulation of local and systemic inflammatory and immune responses is implicated in the pathogenesis of fibrotic and degenerative complications after anterior cruciate ligament reconstruction (ACLR) surgery. In other surgical trauma models, ALM therapy has been shown to blunt inflammation, leading to a more permissive healing environment in injured tissues. The purpose of this study was to evaluate sex-specific effects of surgery and perioperative ALM therapy on leukocyte mobilization and activation, and systemic and joint tissue inflammation in a rat model of ACL rupture and reconstruction. Methods Adult male and female Sprague–Dawley rats were randomly divided into ALM (male, n = 15; female, n = 14) or Saline control (male, n = 13; female, n = 14) treatment groups. Three days after non-invasive ACL rupture, ACLR surgery was performed on the injured knee. Animals received a 1 h perioperative IV ALM or saline drip, and a 0.1 ml IA bolus of ALM or saline, and were monitored to 120 h postoperative. Hematology, leukocyte immunophenotyping, plasma and synovial inflammatory mediator concentrations, and joint tissue histopathology and gene expression of inflammatory markers were assessed. Results Following ACLR surgery, plasma concentrations of inflammatory cytokines IL-6, TNF-α and IL-1β peaked later and at a higher magnitude in females compared to males, with ALM dampening this systemic inflammatory response. At 1 h postoperative, ALM boosted circulating B cell numbers in males and females, and decreased neutrophil activation in females. By 72 h, numbers of circulating T cells with immunoregulatory potential were increased in all ALM-treated animals compared to Saline controls, and corresponded to a significant reduction in synovial TNF-α concentrations within the operated knees. Sex-specific treatment differences were found in inflammatory and immune profiles in the synovial fluid and joint tissues. Inflammatory cell infiltration and gene expression of markers of inflammation (Nfκb, Nlrp3), cytoprotective responses (Nrf2), and angiogenesis (Vegf) were increased in joint synovial tissue from ALM-treated males, compared to controls. In females, ALM treatment was associated with increased mononuclear cell recruitment, and expression of M2 macrophage marker (Arg1) in joint synovial tissue. Conclusions ALM has differential effects on the immuno-inflammatory response of males and females in the early postoperative period after ACLR surgery, with potential implications for subsequent joint tissue repair processes.

Skeletal muscle trauma is a common injury with a range of severity. Adenosine, lidocaine and Mg2+ (ALM) is a protective solution and improves tissue perfusion and coagulopathy. Male Wistar rats were anesthetized and subjected to standardized skeletal muscle trauma of the left soleus muscle with the protection of the neurovascular structures. Seventy animals were randomly assigned to saline control or ALM. Immediately after trauma, a bolus of ALM solution was applied intravenously, followed by a one-hour infusion. After 1, 4, 7, 14 and 42 days, the biomechanical regenerative capacity was examined using incomplete tetanic force and tetany, and immunohistochemistry was used to examine for proliferation and apoptosis characteristics. Biomechanical force development showed a significant increase following ALM therapy for incomplete tetanic force and tetany on days 4 and 7. In addition, the histological evaluation showed a significant increase in proliferative BrdU-positive cells with ALM therapy on days 1 and 14. Ki67 histology also detected significantly more proliferative cells on days 1, 4, 7, 14 and 42 in ALM-treated animals. Furthermore, a simultaneous decrease in the number of apoptotic cells was observed using the TUNEL method. ALM solution showed significant superiority in biomechanical force development and also a significant positive effect on cell proliferation in traumatized skeletal muscle tissue and reduced apoptosis.