Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Abstract

Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of a small-volume 0.9% NaCl adenosine, lidocaine, and Mg 2؉ (ALM) bolus and a 4-h intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to that of controls (25%). Four controls died on day 2 to 3, and two died on day 5. Early death was associated with elevated plasma and lung inflammatory markers (interleukin-6 [IL-6], IL-1␤, C-reactive protein), reduced white blood cell (WBC) count, hypoxemia, hypercapnia, acidosis, hyperkalemia, and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil-dominated WBC rebound/overshoot, increased lung oxidant injury, edema, and persistent ischemia. On day 6, seven of eight ALM survivors had inflammatory and immunological profiles not significantly different from those of sham-treated animals. We conclude in the rat model of experimental sepsis that small-volume ALM treatment led to higher survivability at 6 days (88%) than that of controls (25%). Early death in controls (day 2 to 3) was associated with significantly elevated plasma levels of IL-1␤, IL-6, and C-reactive protein, severe plasma lymphocyte deficiency, reduced neutrophils, and acute lung injury. Late death (day 5) was associated with a massive neutrophil inflammatory storm, increased lung injury, and persistent ischemia. Possible mechanisms of ALM protection are discussed. G lobally, 1,000 people die from sepsis every hour, claiming more lives than trauma, heart attack, or cancer (1-3). Sepsis develops from the host's response to an infection involving an overexpression of systemic inflammation, coagulopathy, immune dysfunction, and eventually multiple-organ failure (4,5). Over the past 2 decades, despite new antimicrobial/antifungal agents and advanced life support systems, the case fatality rate for patients with sepsis has remained at 20% to 30% and up to 50% in lowincome countries (3,4,6). An ongoing concern is why do some patients who receive state-of-the-art treatment die and others live? The reasons are complex but appear to be related to the type and unpredictable nature of pathogen progression (2, 5, 7), the degree of autonomic and cardiac dysfunction that develops (8), and the lack of a suitable frontline drug therapy to protect against the inability of the immune system to discriminate self from non-self, causing widespread tissue injury and eventually death.Previously, we have shown in the rat model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP), that smallvolume adenosine, lidocaine, and Mg 2ϩ (ALM) induced a stable, hypotensive state over 5 h with no arrhythmias, significantly less pulmonary edema, and corrected coagulopathy (9). The ALM concept has also translated to the pig model of lipopolysaccharide endotoxemia (10). In comparison to controls, ALM infusion led to a mild hibernation-like state that decreased mean arterial pres...

Adenosine, lidocaine and Mg2+ (ALM) fluid therapy attenuates systemic inflammation, platelet dysfunction and coagulopathy after non-compressible truncal hemorrhage

“…In partial support of ALM inhibition of inflammasome signaling, we showed that IL-1β and IL-1α were undetected in plasma at Phase 1 compared to saline controls (50 and 205 pg/ml respectively), and only increased to ~5% of control values after Phase 2 ( Table 2 ). ALM's ability to blunt systemic inflammation parallels a separate study we recently published in the rat model of polymicrobial sepsis, where we showed that a 0.9% NaCl ALM saline 'drip' administered for 4 hours (total volume 1.6 ml) led to little or no systemic inflammation and 88% survivability after 6 days with no antibiotics [ 19 ].…”

“…At high (0.25 to 1 mM) concentrations, ALM arrests the heart, and at lower ‘non-arrest’ concentrations (10-fold less), it resuscitates the heart. The 'non-arrest' ALM bolus and infusion 'drip' treatments have been shown to protect rat and pig models against regional myocardial ischemia, lethal arrhythmias, cardiac arrest, hemorrhagic shock, endotoxemia, infection and sepsis [ 15 , 17 – 19 ]. A, L and M alone do not confer these benefits [ 15 ].…”

Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

“…What follows is a characterization of the ALM survival phenotype and why it may be applicable to reduce inflammation from a viral attack. (3,207). ALM survival was associated with suppression of the systemic inflammatory response.…”

“…We will now briefly review our efforts to develop an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg 2+ (ALM) that uniquely protects against trauma and infection, and may be useful as an immune-modulatory agent for coronavirus 2 (SARS-CoV-2), and other viral challenges. Our early experiments focused on traumatic injury (139,(201)(202)(203)(204)(205) and subsequently we showed the same therapy protects against sepsis and endotoxemia in different animal models (3,206,207). The individual effects of A, L or M also have been shown to confer some protection, but not to the same extent as ALM combined (12,208).…”

Immune-inflammatory activation after a single laparotomy in a rat model: effect of adenosine, lidocaine and Mg2+ infusion to dampen the stress response

“…7 The ALM bolus and/or infusion treatments have been shown in rat and pig models to protect against regional myocardial ischemia, lethal arrhythmias, cardiac arrest, hemorrhagic shock, coagulopathy, inflammation, endotoxemia, infection and sepsis. [7][8][9][10][11][12] Adenosine, lidocaine and Mg 2+ alone do not confer these benefits. 7 In the present study, we hypothesized that the low-volume ALM drip/infusion may improve physiologic status in the first few hours following a single laparotomy.…”