Addressing the Global Burden of Trauma in Major Surgery

Despite a technically perfect procedure, surgical stress can determine the success or failure of an operation. Surgical trauma is often referred to as the neglected step-child of global health in terms of patient numbers, mortality, morbidity and costs. A staggering 234 million major surgeries are performed every year, and depending upon country and institution, up to 4% of patients will die before leaving hospital, up to 15% will have serious post-operative morbidity, and 5 to 15% will be readmitted within 30 days. These percentages equate to around 1000 deaths and 4000 major complications every hour, and it has been estimated that 50% may be preventable. New frontline drugs are urgently required to make major surgery safer for the patient and more predictable for the surgeon. We review the basic physiology of the stress response from neuroendocrine to genomic systems, and discuss the paucity of clinical data supporting the use of statins, beta-adrenergic blockers and calcium channel blockers. Since cardiac-related complications are the most common, particularly in the elderly, a key strategy would be to improve ventricular-arterial coupling to safeguard the endothelium and maintain tissue oxygenation. Reduced O2 supply is associated with glycocalyx shedding, decreased endothelial barrier function, fluid leakage, inflammation and coagulopathy. A healthy endothelium may prevent these secondary hit complications, including possibly immunosuppression. Thus the four pillars of whole body resynchronization during surgical trauma, and targets for new therapies, are: 1) the CNS, 2) the heart, 3) arterial supply and venous return functions, and 4) the endothelium. This is termed the Central-Cardio-Vascular-Endothelium (CCVE) coupling hypothesis. Since similar sterile injury cascades exist in critical illness, accidental trauma, hemorrhage, cardiac arrest, infection and burns, new drugs that improve CCVE coupling may find wide utility in civilian and military medicine

Wired to Doubt: Why People Fear Vaccines and Climate Change and Mistrust Science

We all want to be right in our thinking. Vaccine hesitancy and global warming denial share much in common: (1) both are threats to personal, community and global health, (2) action is contingent on co-operation and social policy, and (3) public support relies on trust in science. The irony is, however, as the science has become more convincing, public opinion has become more divided. A number of early polls showed that ~70% of people supported COVID-19 vaccine use and global warming, ~20% adopted a wait-and-see approach, and ~10% were staunch objectors. Although these percentages are approximate, what factors are responsible for the differences in engagement, doubt and distrust? How can we reduce the consensus gap? One approach is to return to grass roots and provide a brief history of the issues, understand the difference between fact and opinion, truth and falsehood, the problem of certainty, and how scientific consensus is reached. To doubt is a healthy response to new information, and it too has a scientific basis. Doubt and distrust reside in that region of the brain called the dorsolateral prefrontal cortex, which is responsible for suppressing unwanted representations. Bridging the consensus gap requires shifting human thinking patterns from doubt to belief, and belief to action. Education and improved public messaging are key, and social media providers require urgent oversight or regulation to remove false and harmful/dangerous content from our digital lives. Delays to vaccinate and failure to reduce greenhouse gases will dramatically change the way we live. The new norm may be more deadly COVID variants, strained healthcare systems, extreme weather patterns, diminished food supply, delays in goods and services, damage to world's economies and widespread global instability

Science and the War on Truth and coronavirus

[Extract] I am a scientist and this is my brief on what the world needs to know about science and COVID-19. Science is a method of truth-telling about the physical world and ways to improve quality of life. It is the most powerful enterprise that has led to improved healthcare, a more sustainable environment, a safer world, and a better “knowing and understanding” about the world we live in. Science is fun and spectacular. And it has rarely let us down, until now. Despite multiple warnings in 2015, the current global pandemic has revealed major deficits in our preparedness for a viral attack. Governments have let the public down by not supporting early warning programs and for not providing sufficient science funding to understand how different people respond differently to a viral attack, and vaccine development. The present pandemic has also revealed that science underpins a country's national security in ways never appreciated before. The resultant economic upheaval has thrown global supply chains, stock markets, the airline industry, oil markets, and the central bank into frenzied disarray (1). It is regrettable that it took a global pandemic, and the most powerful global economies to come crashing to their knees, with hundreds of thousands of lives lost, to bring science out of the shadows, and into the spotlight

Adenosine relaxation in isolated rat aortic rings and possible roles of smooth muscle Kv channels, KATP channels and A2a receptors.

Background: An area of ongoing controversy is the role adenosine to regulate vascular tone in conduit vessels that regulate compliance, and the role of nitric oxide (NO), potassium channels and receptor subtypes involved. The aim of our study was to investigate adenosine relaxation in rat thoracic aortic rings, and the effect of inhibitors of NO, prostanoids, Kv, KATP channels, and A2a and A2b receptors. Methods: Aortic rings were freshly harvested from adult male Sprague Dawley rats and equilibrated in an organ bath containing oxygenated, modified Krebs-Henseleit solution, 11 mM glucose, pH 7.4, 37 °C. Isolated rings were pre-contracted sub-maximally with 0.3 μM norepinephrine (NE), and the effect of increasing concentrations of adenosine (1 to 1000 μM) were examined. The drugs L-NAME, indomethacin, 4-aminopyridine (4-AP), glibenclamide, 5-hydroxydecanoate, ouabain, 8-(3-chlorostyryl) caffeine and PSB-0788 were examined in intact and denuded rings. Rings were tested for viability after each experiment. RESULTS: Adenosine induced a dose-dependent, triphasic relaxation response, and the mechanical removal of the endothelium significantly deceased adenosine relaxation above 10 μM. Interestingly, endothelial removal significantly decreased the responsiveness (defined as % relaxation per μM adenosine) by two-thirds between 10 and 100 μM, but not in the lower (1-10 μM) or higher (>100 μM) ranges. In intact rings, L-NAME significantly reduced relaxation, but not indomethacin. Antagonists of voltage-dependent Kv (4-AP), sarcolemma KATP (glibenclamide) and mitochondrial KATP channels (5-HD) led to significant reductions in relaxation in both intact and denuded rings, with ouabain having little or no effect. Adenosine-induced relaxation appeared to involve the A2a receptor, but not the A2b subtype. Conclusions:It was concluded that adenosine relaxation in NE-precontracted rat aortic rings was triphasic and endothelium-dependent above 10 μM, and relaxation involved endothelial nitric oxide (not prostanoids) and a complex interplay between smooth muscle A2a subtype and voltage-dependent Kv, SarcKATP and MitoKATP channels. The possible in vivo significance of the regulation of arterial compliance to left ventricular function coupling is discussed

Lidocaine relaxation in isolated rat aortic rings is enhanced by endothelial removal: possible role of Kv, KATP channels and A2a receptor crosstalk

Background: Lidocaine is an approved local anesthetic and Class 1B antiarrhythmic with a number of ancillary properties. Our aim was to investigate lidocaine's vasoreactivity properties in intact versus denuded rat thoracic aortic rings, and the effect of inhibitors of nitric oxide (NO), prostenoids, voltage-dependent Kv and KATP channels, membrane Na+/K+ pump, and A2a and A2b receptors. Methods: Aortic rings were harvested from adult male Sprague Dawley rats and equilibrated in an organ bath containing oxygenated, modified Krebs-Henseleit solution, pH 7.4, 37 °C. The rings were pre-contracted sub-maximally with 0.3 μM norepinephrine (NE), and the effect of increasing lidocaine concentrations was examined. Rings were tested for viability after each experiment with maximally dilating 100 μM papaverine. The drugs 4-aminopyridine (4-AP), glibenclamide, 5-hydroxydecanoate, ouabain, 8-(3-chlorostyryl) caffeine and PSB-0788 were examined. Results: All drugs tested had no significant effect on basal tension. Lidocaine relaxation in intact rings was biphasic between 1 and 10 μM (Phase 1) and 10 and 1000 μM (Phase 2). Mechanical removal of the endothelium resulted in further relaxation, and at lower concentrations ring sensitivity (% relaxation per μM lidocaine) significantly increased 3.5 times compared to intact rings. The relaxing factor(s) responsible for enhancing ring relaxation did not appear to be NO- or prostacyclin-dependent, as L-NAME and indomethacin had little or no effect on intact ring relaxation. In denuded rings, lidocaine relaxation was completely abolished by Kv channel inhibition and significantly reduced by antagonists of the MitoKATP channel, and to a lesser extent the SarcKATP channel. Curiously, A2a subtype receptor antagonism significantly inhibited lidocaine relaxation above 100 μM, but not the A2b receptor

The role of nitric oxide in the efficacy of adenosine, lidocaine and magnesium (ALM) treatment of experimental hemorrhagic shock in rats

Background: Since nitric oxide (NO) plays multiple roles regulating the central nervous, cardiovascular and immune systems, our aim was to investigate the role of NO in the efficacy of 7.5% NaCl adenosine, lidocaine and magnesium (ALM) to improve mean arterial pressure (MAP) and heart rate (HR) following hemorrhagic shock (HS). Methods: Male Sprague-Dawley rats (101; 425±6g) were randomly assigned to 20 groups (n=4-n=8). HS (MAP<40mmHg) was induced by 20min pressure-controlled bleeding (∼40% blood volume), and the animal was left in shock (MAP 35-40mmHg) for 60min. NO synthase (NOS) inhibitor L-NAME was administered with a 0.3ml bolus of different combinations of 7.5% NaCl ALM active ingredients and hemodynamics were monitored for 60min. A number of specific NOS and NO inhibitors were tested. Results: 7.5% NaCl ALM corrected MAP after HS. In contrast, the addition of L-NAME to 7.5% NaCl ALM led to a rapid fall in MAP, sustained ventricular arrhythmias, and 100% mortality. Saline controls receiving 7.5% NaCl with L-NAME showed improved MAP with no deaths. None of the specific NOS and NO inhibitors mimicked L-NAME's effect on ALM. The addition of inducible (iNOS) inhibitor 1400W to 7.5% NaCl ALM failed to resuscitate, while NO scavenger PTIO and PI3K inhibitor Wortmannin reduced MAP recovery during 60min resuscitation. Conclusions: The ability of 7.5% NaCl ALM to resuscitate appears to be linked to one or more NO-producing pathways. Non-specific NOS inhibition with L-NAME blocked ALM resuscitation and led to cardiovascular collapse. More studies are required to examine NO site-specific contributions to ALM resuscitation

The adenosine hypothesis revisited: modulation of coupling between myocardial perfusion and arterial compliance

For over four decades the thoracic aortic ring model has become one of the most widely used methods to study vascular reactivity and electromechanical coupling. A question that is rarely asked, however, is what function does a drug-mediated relaxation (or contraction) in this model serve in the intact system? The physiological significance of adenosine relaxation in rings isolated from large elastic conduit arteries from a wide range of species remains largely unknown. We propose that adenosine relaxation increases aortic compliance in acute stress states and facilitates ventricular-arterial (VA) coupling, and thereby links compliance and coronary artery perfusion to myocardial energy metabolism. In 1963 Berne argued that adenosine acts as a local negative feedback regulator between oxygen supply and demand in the heart during hypoxic/ischemic stress. The adenosine VA coupling hypothesis extends and enhances Berne's “adenosine hypothesis” from a local regulatory scheme in the heart to include conduit arterial function. In multicellular organisms, evolution may have selected adenosine, nitric oxide, and other vascular mediators, to modulate VA coupling for optimal transfer of oxygen (and nutrients) from the lung, heart, large conduit arteries, arterioles and capillaries to respiring mitochondria. Finally, a discussion of the potential clinical significance of adenosine modulation of VA coupling is extended to vascular aging and disease, including hypertension, diabetes, obesity, coronary artery disease and heart failure

Adenosine and lidocaine (AL) combination dilates intimally damaged rat thoracic aortic rings and guinea pig mesenteric arteries: possible significance to cardiac surgery

New pharmacotherapies are required to improve vessel graft protection and prevent vasoconstriction and spasm in CABG surgery. Previously we have studied adenosine (A) and lidocaine (L) relaxation in rat aortic rings, and reported a possible crosstalk between L relaxation and adenosine A(2a) receptor inhibition. The aim of the present study was to examine the effect of AL combination compared to A and L alone on relaxation in intact and denuded rat aortic rings and in guinea-pig pressurized mesenteric arterial segments. Aortic rings were harvested from Sprague-Dawley rats and equilibrated in an organ bath containing modified Krebs-Henseleit (KH) solution, pH 7.4, 37 degrees C. Rings were pre-contracted sub-maximally with 0.3 mu M norepinephrine, and the effects of increasing AL, A or L (up to 1.0 mM) were examined in intact and denuded rings. Mesenteric artery segments were isolated from guinea-pigs and mounted in an arteriograph containing KH solution and pressurised to 60 mmHg. Arteries were preconstricted with 10(-8) M vasopressin and AL, A, or L was administered luminally or abluminally. Diameters were measured using video-microscopy. We report in intact rat aortic rings, AL increased relaxation from 21 to 100% (0.1-1.0 mM) and relaxation was endothelium-independent. Adenosine alone was also a potent relaxant of aortic rings but, unlike AL relaxation, it was partially endothelium-dependent. In intact mesenteric artery segments, increasing luminal AL produced a potent endothelium-independent dilation (up to 90%). Adenosine dilation was endothelium-independent but not lidocaine, which produced 33% dilation only after endothelial removal. Extra-luminal AL and A led to 76% and 80% dilationin intact segments respectively, whereas L resulted in constriction (10-17%). In conclusion, we show that AL can dilate aortic rings and mesenteric artery segments by up to 90% regardless of whether the endothelium is intact. We discuss the potential translational significance of AL to improve conduit protection in cardiac surgery, and other major surgeries

Clinical relevance of a p value: Does tranexamic acid save lives after trauma or postpartum hemorrhage?

[Extract] Tranexamic acid (TXA), an antifibrinolytic agent, has been widely publicized as saving lives after traumatic hemorrhage in the CRASH-2, MSATTERs, and PER-TRAX trials (2-5) and more recently after postpartum hemorrhage (PPH) in the World Maternal Antifibrinolytic (WOMAN) trial (6). Prophylactic administration of TXA is also increasingly used in major elective and emergency surgery to reduce excessive bleeding, transfusion requirements, and possible reexploration. (7

Thermodynamics of the pyruvate kinase reaction and the reversal of glycolysis in heart and skeletal muscle

The effect of temperature, pH, and free [Mg2+] on the apparent equilibrium constant of pyruvate kinase (phosphoenol transphosphorylase) (EC 2.7.1.40) was investigated. The apparent equilibrium constant, K', for the biochemical reaction P-enolpyruvate + ADP = ATP + Pyr was defined as K' = [ATP][Pyr]/[ADP][P-enolpyruvate], where each reactant represents the sum of all the ionic and metal complexed species in M. The K' at pH 7.0, 1.0 mM free Mg2+ and I of 0.25 M was 3.89 × 104 (n = 8) at 25 °C. The standard apparent enthalpy (Delta H'°) for the biochemical reaction was -4.31 kJmol-1 in the direction of ATP formation. The corresponding standard apparent entropy (Delta S'°) was +73.4 J K-1 mol-1. The Delta H° and Delta S° values for the reference reaction, P-enolpyruvate3- + ADP3- + H+ = ATP4- + Pyr1-, were -6.43 kJmol-1 and +180 J K-1 mol-1, respectively (5 to 38 °C). We examined further the mass action ratio in rat heart and skeletal muscle at rest and found that the pyruvate kinase reaction in vivo was close to equilibrium i.e. within a factor of about 3 to 6 of K' in the direction of ATP at the same pH, free [Mg2+], and T. We conclude that the pyruvate kinase reaction may be reversed under some conditions in vivo, a finding that challenges the long held dogma that the reaction is displaced far from equilibrium