Hayley L. Letson

Mechanisms of early trauma-induced coagulopathy: The clot thickens or not?

Abstract Traumatic-induced coagulopathy (TIC) is a hemostatic disorder that is associated with significant bleeding, transfusion requirements, morbidity and mortality. A disorder similar or analogous to TIC was reported around 70 years ago in patients with shock, hemorrhage, burns, cardiac arrest or undergoing major surgery, and the condition was referred to as a “severe bleeding tendency,” “defibrination syndrome,” “consumptive disorder,” and later by surgeons treating US Vietnam combat casualties as a “diffuse oozing coagulopathy.” In 1982, Moore’s group termed it the “bloody vicious cycle,” others “the lethal triad,” and in 2003 Brohi and colleagues introduced “acute traumatic coagulopathy” (ATC). Since that time, early TIC has been cloaked in many names and acronyms, including a “fibrinolytic form of disseminated intravascular coagulopathy (DIC).” A global consensus on naming is urgently required to avoid confusion. In our view, TIC is a dynamic entity that evolves over time and no single hypothesis adequately explains the different manifestations of the coagulopathy. However, early TIC is not DIC because an increased thrombin-generating potential in vitro does not imply a clinically relevant thrombotic state in vivo as early TIC is characterized by excessive bleeding, not thrombosis. DIC with its diffuse anatomopathologic fibrin deposition appears to be a latter phase progression of TIC associated with unchecked inflammation and multiple organ dysfunction.

Reversal of acute coagulopathy during hypotensive resuscitation using small-volume 7.5% NaCl adenocaine and Mg2+ in the rat model of severe hemorrhagic shock

Objective: Acute traumatic coagulopathy occurs early in hemorrhagic trauma and is a major contributor to mortality and morbidity. Our aim was to examine the effect of small-volume 7.5% NaCl adenocaine (adenosine and lidocaine, adenocaine) and Mg2+ on hypotensive resuscitation and coagulopathy in the rat model of severe hemorrhagic shock. Design: Prospective randomized laboratory investigation. Subjects: A total of 68 male Sprague Dawley Rats. Intervention: Post-hemorrhagic shock treatment for acute traumatic coagulopathy. Measurements and Methods: Nonheparinized male Sprague-Dawley rats (300–450 g, n = 68) were randomly assigned to either: 1) untreated; 2) 7.5% NaCl; 3) 7.5% NaCl adenocaine; 4) 7.5% NaCl Mg2+; or 5) 7.5% NaCl adenocaine/Mg2+. Hemorrhagic shock was induced by phlebotomy to mean arterial pressure of 35–40 mm Hg for 20 mins (~40% blood loss), and animals were left in shock for 60 mins. Bolus (0.3 mL) was injected into the femoral vein and hemodynamics monitored. Blood was collected in Na citrate (3.2%) tubes, centrifuged, and the plasma snap frozen in liquid N2 and stored at −80°C. Coagulation was assessed using activated partial thromboplastin times and prothrombin times. Results: Small-volume 7.5% NaCl adenocaine and 7.5% NaCl adenocaine/Mg2+ were the only two groups that gradually increased mean arterial pressure 1.6-fold from 38–39 mm Hg to 52 and 64 mm Hg, respectively, at 60 mins (p < .05). Baseline plasma activated partial thromboplastin time was 17 ± 0.5 secs and increased to 63 ± 21 secs after bleeding time, and 217 ± 32 secs after 60-min shock. At 60-min resuscitation, activated partial thromboplastin time values for untreated, 7.5% NaCl, 7.5% NaCl/Mg2+, and 7.5% NaCl adenocaine rats were 269 ± 31 secs, 262 ± 38 secs, 150 ± 43 secs, and 244 ± 38 secs, respectively. In contrast, activated partial thromboplastin time for 7.5% NaCl adenocaine/Mg2+ was 24 ± 2 secs (p < .05). Baseline prothrombin time was 28 ± 0.8 secs (n = 8) and followed a similar pattern of correction. Conclusions: Plasma activated partial thromboplastin time and prothrombin time increased over 10-fold during the bleed and shock periods prior to resuscitation, and a small-volume (~1 mL/kg) IV bolus of 7.5% NaCl AL/Mg2+ was the only treatment group that raised mean arterial pressure into the permissive range and returned activated partial thromboplastin time and prothrombin time clotting times to baseline at 60 mins.

Unexpected 100% survival following 60% blood loss using small-volume 7.5% NaCl with Adenocaine and mg2+ in the rat model of extreme hemorrhagic shock

ABSTRACT Hemorrhage is responsible for up to 40% of trauma mortality, and of these deaths, 33% to 56% occur during the prehospital period. In an effort to translate the cardioprotective effects of Adenocaine (adenosine, lidocaine) and Mg2+ (ALM) from cardiac surgery to resuscitation science, we examined the early resuscitative effects of 7.5% NaCl with ALM in the rat model of 60% blood loss. Male Sprague-Dawley rats (250–350 g, n = 40) were anesthetized and randomly assigned to one of five groups: (a) untreated, (b) 7.5% NaCl, (c) 7.5% NaCl/6% dextran 70, (d) 7.5% NaCl/Mg2+, and (e) 7.5% NaCl/ALM. Blood withdrawal occurred over ∼50 min (MAP 30–35 mmHg), and rats were left in shock for 30 min. Total shock time was ∼80 min; 0.3-mL bolus was injected intravenously over 10 s, and hemodynamics monitored for 60 min (phase 1). Shed blood was reinfused and function monitored for a further 60 min (phase 2). Lead II electrocardiogram, arterial pressures, mean arterial pressure (MAP), pulse pressure (PP), heart rate (HR), and rate-pressure product were monitored. Mortality was as follows: untreated (100%), 7.5% NaCl (75%), 7.5% NaCl/6% dextran 70 (87.5%), 7.5% NaCl/Mg2+ (62.5%), and 7.5% NaCl/ALM (0%). Deaths occurred at different times depending on treatment group and paralleled differences in the total number of ventricular arrhythmias with the highest number in untreated animals (49 ± 17) and lowest in 7.5% NaCl/ALM rats (2 ± 1.8) (P < 0.05). At the end of phase 1, MAP of 7.5% NaCl/ALM–treated animals increased from 29 to 40 mmHg (P < 0.05). At the end of phase 2, MAP, PP, HR, and rate-pressure product in the ALM group were 75%, 193%, 96%, and 83% of their preshock values. Small-volume (∼1 mL/kg) i.v. bolus of 7.5% NaCl/ALM led to 100% survival following 60% blood loss with higher MAP than any group, an 89% to 96% reduction in the total number of arrhythmias, and a stable HR.

Correction of acute traumatic coagulopathy with small-volume 7.5% Nacl adenosine, lidocaine, and Mg2+ occurs within 5 minutes: A Rotem analysis

BACKGROUND Acute traumatic coagulopathy is a major contributor to mortality and morbidity following hemorrhagic shock. Our aim was to examine the effect of small-volume 7.5% NaCl with adenosine, lidocaine, and Mg2+ (ALM) resuscitation on the timing of correction of coagulopathy in the rat model of severe hemorrhagic shock using ROTEM. METHODS Male rats (300–450 g, n = 64) were randomly assigned to (1) baseline, (2) sham, (3) bleed, (4) shock, (5) 7.5% NaCl for 5 minutes, (6) 7.5% NaCl with ALM for 5 minutes, (7) 7.5% NaCl for 60 minutes, or (8) 7.5% NaCl with ALM for 60 minutes (all n = 8). For resuscitation, 0.3-mL intravenous bolus of 7.5% NaCl was administered with and without ALM (n = 8 each group). Hemodynamics and coagulopathy were assessed. RESULTS After hemorrhage, prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased approximately four to six times, and ROTEM indicated hypocoagulopathy. After 60-minute shock, no sustainable clots could form. 7.5% NaCl increased mean arterial pressure (MAP) to 46 ± 2 mm Hg at 5 minutes and generated a weak clot in EXTEM with hyperfibrinolysis in all tests. At 60 minutes, 7.5% NaCl failed to sustain MAP (43 ± 5 mm Hg) and generate a viable clot. In direct contrast, 7.5% NaCl with ALM at 5 minutes resuscitated MAP to 64 ± 3 mm Hg, corrected PT and aPTT, and generated fully formed EXTEM and FIBTEM clots. At 60 minutes, MAP was 69 ± 5 mm Hg, PT and aPTT were fully corrected, and &agr; angle, clot amplitudes (A10, A30), as well as clot firmness and elasticity were not significantly different from baseline. ALM clot lysis at 60 minutes was significantly less than bleed, shock, or 7.5% NaCl, indicating protection against hyperfibrinolysis. CONCLUSION Small-volume 7.5% NaCl failed to resuscitate and correct coagulopathy. In contrast, 7.5% NaCl with ALM resuscitated MAP and corrected coagulopathy at 5 minutes, with further improvements at 60 minutes in clot kinetics, propagation, and firmness. ALM fully reversed hyperfibrinolysis to baseline. The possible mechanisms are discussed.

Ultra-small intravenous bolus of 7.5% NaCl/Mg2+ with adenosine and lidocaine improves early resuscitation outcome in the rat after severe hemorrhagic shock in vivo

OBJECTIVE Much controversy exists over the fluid composition for hypotensive resuscitation. We previously showed that addition of 6% Dextran-70 or hetastarch to 7.5% NaCl led to heart instability and mortality. Our aim was to examine the early resuscitative effects of 7.5% NaCl with adenosine, lidocaine, and magnesium (ALM) on hemodynamics and mortality in a rat model of severe hemorrhagic shock. METHODS Male fed Sprague-Dawley rats (300-450 g, n = 48) were anesthetized and randomly assigned to one of six groups (n = 8): (1) Untreated, (2) 7.5% saline, (3) 7.5% NaCl/Mg²⁺, (4) 7.5% NaCl with adenosine/Mg²⁺, (5) 7.5% NaCl with lidocaine/Mg²⁺, and (6) 7.5% NaCl/ALM. Hemorrhagic shock was induced by phlebotomy until mean arterial pressure (MAP) was 35 mm Hg to 40 mm Hg and continued for 20 minutes (40% blood loss). Animals were left in shock for 60 minutes at 34°C. 0.3 mL (~3.5% of shed blood) was injected as a 10-second bolus into the femoral vein. Lead II electrocardiography, arterial pressures, MAP, heart rate, and rate-pressure product were monitored. RESULTS Untreated rats experienced severe arrhythmias and 38% mortality. There were no other deaths. 7.5% NaCl alone failed to maintain MAP after 5 minutes and was significantly improved with Mg²⁺. At 60 minutes, the MAP for 7.5% NaCl alone was 36 mm Hg compared with 48 mm Hg for the magnesium group. 7.5% NaCl/ALM led to a significantly higher MAP (57-60 mm Hg at 45-60 minutes). The higher MAP was associated with up to a 2-fold increase in arterial diastolic pressure. Both 7.5% NaCl with adenosine/Mg²⁺ and lidocaine/Mg²⁺ were mildly bradycardic but not when combined as ALM. A few arrhythmias occurred in 7.5% NaCl group with or without Mg, but no arrhythmias occurred in the other treatment groups. CONCLUSION Ultra-small intravenous bolus of 7.5% NaCl with ALM led to a significantly higher MAP, higher diastolic rescue, and higher rate-pressure product compared with other treatment groups. The possible clinical and military applications for permissive hypotensive resuscitation are discussed.

Adenosine, lidocaine, and Mg2+ (ALM™) increases survival and corrects coagulopathy after eight-minute asphyxial cardiac arrest in the rat.

Abstract Introduction: No drug therapy has demonstrated improved survival following cardiac arrest (CA) of cardiac or noncardiac origin. In an effort to translate the cardiorescue properties of Adenocaine (adenosine and lidocaine) and magnesium sulfate (ALM) from cardiac surgery and hemorrhagic shock to resuscitation, we examined the effect of ALM on hemodynamic rescue and coagulopathy following asphyxial-induced CA in the rat. Methods: Nonheparinized animals (400–500 g, n = 39) were randomly assigned to 0.9% saline (n = 12) and 0.9% saline ALM (n = 10) groups. After baseline data were acquired, the animal was surface cooled (33°C–34°C) and the ventilator line clamped for 8 min inducing CA; 0.5 mL of solution was injected intravenously followed by 60-s chest compressions (300/min), and rats were rewarmed. Return of spontaneous circulation (ROSC), mean arterial pressure, heart rate, and rectal temperature were recorded for 2 h. Additional rats were randomized for rotation thromboelastometry measurements (n = 17). Results: Rats treated with ALM had a significant survival benefit (100% ALM vs. 67% controls achieved ROSC) and generated a higher mean arterial pressure than did controls after 75 min (81 vs. 72 mmHg at 120 min, P < 0.05). In all rats, rotation thromboelastometry lysis index decreased during CA, implying hyperfibrinolysis. Control ROSC survivors displayed hypocoagulopathy (prolonged EXTEM/INTEM clotting time, clot formation time, prothrombin time, activated partial thromboplastin time), decreased maximal clot firmness, lowered elasticity, and lowered clot amplitudes but no change in lysis index. These coagulation abnormalities were corrected by ALM at 120 min after ROSC. Conclusions: Small bolus of 0.9% NaCl ALM improved survival and hemodynamics following nonhemorrhagic, asphyxial CA and corrected prolonged clot times and clot retraction compared with controls.

Adenosine, lidocaine, and Mg2+ (ALM): From cardiac surgery to combat casualty care--Teaching old drugs new tricks.

ABSTRACT New frontline drugs and therapies are urgently required to protect the body from primary and secondary injuries. We review more than 10 years of work on adenosine, lidocaine, and magnesium (ALM) and its possible significance to civilian and military medicine. Adenosine is an endogenous nucleoside involved in nucleotide production, adenosine triphosphate turnover, and restoration of supply and demand imbalances. Lidocaine is a local anesthetic and Class 1B antiarrhythmic, and magnesium is essential for ionic regulation and cellular bioenergetics. Individually, each plays important roles in metabolism, immunomodulation, inflammation, and coagulation. The original idea to combine all three was as a “polarizing” cardioplegia, an idea borrowed from natural hibernators. Two recent prospective, randomized human trials have demonstrated its safety and superiority in myocardial protection over high-potassium “depolarizing” solutions. The next idea came from witnessing how the human heart spontaneously reanimated after complex operations with little inotropic support. At high doses, ALM arrests the heart, and at lower doses, it resuscitates the heart. In rat and pig models, we have shown that ALM intravenous bolus and infusion “drip” protects against acute regional myocardial ischemia, lethal arrhythmias, cardiac arrest, compressible and noncompressible blood loss and shock, endotoxemia, and sepsis. Individually, adenosine, lidocaine, or magnesium fails to protect. Protection is afforded in part by reducing inflammation, correcting coagulopathy, and lowering energy demand. We propose a unifying hypothesis involving improved central, cardiovascular and endothelium coupling to maintain sufficient tissue oxygenation and reduce primary and secondary “hit” complications. As with any new drug innovation, translation into humans is challenging.

Small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ has multiple benefits during hypotensive and blood resuscitation in the pig following severe blood loss: rat to pig translation.

Objectives:Currently, there is no effective small-volume fluid for traumatic hemorrhagic shock. Our objective was to translate small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ hypotensive fluid resuscitation from the rat to the pig. Design:Pigs (35–40 kg) were anesthetized and bled to mean arterial pressure of 35–40 mm Hg for 90 minutes, followed by 60 minutes of hypotensive resuscitation and infusion of shed blood. Data were collected continuously. Setting:University hospital laboratory. Subjects:Female farm-bred pigs. InterventionsPigs were randomly assigned to a single IV bolus of 4 mL/kg 7.5% NaCl + adenosine, lidocaine and Mg+2 (n = 8) or 4 mL/kg 7.5% NaCl (n = 8) at hypotensive resuscitation and 0.9% NaCl ± adenosine and lidocaine at infusion of shed blood. Measurements and Main Results:At 60 minutes of hypotensive resuscitation, treatment with 7.5% NaCl + adenosine, lidocaine, and Mg2+ generated significantly higher mean arterial pressure (48 mm Hg [95% CI, 44–52] vs 33 mm Hg [95% CI, 30–36], p < 0.0001), cardiac index (76 mL/min/kg [95% CI, 63–91] vs 47 mL/min/kg [95% CI, 39–57], p = 0.002), and oxygen delivery (7.6 mL O2/min/kg [95% CI, 6.4–9.0] vs 5.2 mL O2/min/kg [95% CI, 4.4–6.2], p = 0.003) when compared with controls. Pigs that received adenosine, lidocaine, and Mg2+/adenosine and lidocaine also had significantly lower blood lactate (7.1 mM [95% CI, 5.7–8.9] vs 11.3 mM [95% CI, 9.0–14.1], p = 0.004), core body temperature (39.3°C [95% CI, 39.0–39.5] vs 39.7°C [95% CI, 39.4–39.9]), and higher base excess (–5.9 mEq/L [95% CI, –8.0 to –3.8] vs –11.2 mEq/L [95% CI, –13.4 to –9.1]). One control died from cardiovascular collapse. Higher cardiac index in the adenosine, lidocaine, and Mg2+/adenosine and lidocaine group was due to a two-fold increase in stroke volume. Left ventricular systolic ejection times were significantly higher and inversely related to heart rate in the adenosine, lidocaine, and Mg2+/adenosine and lidocaine group. Thirty minutes after blood return, whole-body oxygen consumption decreased in pigs that received adenosine, lidocaine, and Mg2+/adenosine and lidocaine (5.7 mL O2/min/kg [95% CI, 4.7–6.8] to 4.9 mL O2/min/kg [95% CI, 4.2–5.8]), whereas it increased in controls (4.2 mL O2/min/kg [95% CI, 3.5–5.0] to 5.8 mL O2/min/kg [95% CI, 4.9–5.8], p = 0.02). After 180 minutes, pigs in the adenosine, lidocaine, and Mg2+/adenosine and lidocaine group had three-fold higher urinary output (2.1 mL//kg/hr [95% CI, 1.2–3.8] vs 0.7 mL//kg/hr [95% CI, 0.4–1.2], p = 0.001) and lower plasma creatinine levels. Conclusion:Small-volume resuscitation with 7.5% NaCl + adenosine, lidocaine, and Mg2+/adenosine and lidocaine provided superior cardiovascular, acid-base, metabolic, and renal recoveries following severe hemorrhagic shock in the pig compared with 7.5% NaCl alone.

Adenosine, lidocaine and Mg2+ (ALM) induces a reversible hypotensive state, reduces lung edema and prevents coagulopathy in the rat model of polymicrobial sepsis.

BACKGROUND No drug therapy has demonstrated improved clinical outcomes in the treatment of sepsis. A bolus of adenosine, lidocaine, and magnesium (ALM) has been shown to be cardioprotective and restore coagulopathy in different trauma states. We hypothesized that ALM therapy may improve hemodynamics, protect the lung, and prevent coagulopathy in the rat sepsis model. METHODS Nonheparinized, anesthetized Sprague-Dawley rats (350–450 g, n = 32) were randomly assigned to (1) shams (without sepsis), (2) saline controls, and (3) ALM treatment. Sepsis was induced by cecal ligation and puncture. A 0.3-mL bolus was administered intravenously, followed by a 4-hour intravenous infusion (1 mL/kg/h), and hemodynamics (mean arterial pressure [MAP], systolic arterial pressure, diastolic arterial pressure, and heart rate [HR]) and body temperature (BT) were monitored. Coagulation was assessed using prothrombin time and activated partial thromboplastin time (aPTT). RESULTS Shams displayed progressive falls in MAP, HR, and BT as well as a prolonged aPTT, which were related to surgery, not infection. At 4 hours, controls showed more pronounced falls in MAP (33%), HR (17%), and BT (3.3°C), and MAP continued to fall after the infusion was stopped. In contrast, ALM treatment resulted in a rapid fall in MAP from 111 mm Hg to 73 mm Hg at 30 minutes (p < 0.05 all groups) and was 59 mm Hg at 240 minutes (p < 0.05 shams), which immediately corrected after 4 hours (p < 0.05 controls). HR paralleled MAP changes in ALM rats, and BT was significantly higher than that of the controls but not that of shams. ALM rats had no arrhythmias compared with the controls or shams and had significantly lower lung wet-dry ratios. Prothrombin time in saline controls at 1 hour and 5 hours was prolonged but not in the shams or ALM rats. aPTT at 1 hour in the sham, control, and ALM groups was 158 ± 41 seconds, 161 ± 41 seconds, and 54 ± 23 seconds and at 5 hours was 104 ± 43 seconds, 205 ± 40 seconds, and 33 ± 3 seconds (p < 0.05), respectively. CONCLUSION An ALM bolus/infusion induces a stable, hypotensive hemodynamic state with no arrhythmias, significantly less pulmonary edema, and a higher BT and prevents coagulopathy compared with the controls.

Small-Volume Adenosine, Lidocaine, and Mg2+ 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 Mg2+ (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-1β, 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-1β, 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.