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Tracey, Kevin J. MD

doi: 10.1097/SHK.0b013e3181dc3d4b

Feinstein Institute, Manhasset, New York

The current field of shock research originated with the discovery of the circulatory system by William Harvey. In 1628, at age 50, he published Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (1). This completely overturned the dogma espoused by Galen, taught by Hippocrates, practiced by physicians, and believed by scientists and philosophers for more than 1,300 years. The dogma taught that there were 2 circulatory systems: the heart and arteries, which were responsible for providing vital spirit and life-giving properties to the body, and the veins and liver, which produced blood in the liver and passed it via the veins to the cardiac right ventricle, where it was consumed. A small amount of venous nutrient blood traversed pores in the interventricular septum, passing from the right into the left ventricle. There it combined with the arterial life force, absorbed from the lungs, which generated a pulsing action that propelled blood into the arteries. Other than leakage across the interventricular septum, the arterial and venous blood systems were autonomous circulations and were not connected. Harvey's tome erased the ancient (and revered) dogma, replaced it with a new theory that established the foundation for modern physiology and experimental medicine, and identified operative principals that remain essentially without modification to the present. Harvey made 3 references to "shock" in de Motu, referring not, of course, to the currently used medical definition. Rather, he used it to characterize his observations on the motion of blood to the arteries, which, when mechanically compressed, caused distal branches of the artery to beat less forcibly, as in ".… pulse of the arteries is nothing more than the impulse or shock of the blood in these vessels."

Three hundred sixty-two years later, the pages of the journal Shock have a special place in disseminating the observations of investigators interested in the physiological and molecular mechanisms of the cardiovascular responses to injury and infection. Harvey makes direct reference to the lethality of arterial hemorrhage, describing the "cutting the throat of an ox and so dividing the vessels of the neck" at the butcher's shop, and much less fortunately, at the Chirurgion's quarters, where "the same thing also occasionally occurs with great rapidity in performing amputations and removing tumors in the human subject." In this vein (forgive me), 2 articles in this issue of Shock address modern assessment of circulatory function and performance. Lee et al. (2), who studied the pulse pressure power spectrum in swine subjected to hemorrhagic shock and ventilated mechanically, conclude that this method, based on the reconstruction of beat-to-beat arterial pulse power signals resampled as 4 data points per second for subsequent power spectrum analysis, can be used to predict volume responsiveness during shock with concomitant mechanical ventilator support. This contributes to a developing hypothesis, which may now be further refined and assessed for monitoring resuscitation in the clinic. Mittal et al. (3), in the other article, applied cyclic voltammetry methods to measure changes in serum redox status after hemorrhagic shock and acute pancreatitis. By adapting methods used in the food industry, they used a 3-electrode system to show that this modality can detect changes in serum redox potentials, enabling them to propose the possibility for development of a real-time bedside device. Sharma and Mongan (4) assessed the effects of treating hemorrhagic shock by resuscitating with solutions of hypertonic sodium pyruvate and ethyl pyruvate. The former approach was associated with protection against liver injury and reduced expression of cytokines and stress-related and apoptotic signaling proteins, suggesting the importance of long-term outcome studies to assess these beneficial effects.

In de Motu, Chapter VII, entitled "The Blood Passes Through The Substance Of The Lungs: From The Right Ventricle Of The Heart Into The Pulmonary Veins And Left Ventricle," Harvey specifically overturned the millennium-long belief that the venous and arterial systems were autonomous. For a span of more than a decade, he made observations using a variety of tools, including measuring the total blood volumes lost from exsanguination studies, calculating the volumes of blood capable of passing through the left ventricle and through isolated venous segments (which exceeded the quantity of daily nutrient consumption), and mapping the interrelationships of the pulmonary vessels and heart. He concluded (bravely, as he knew that his work would render him subject to vociferous scorn and punitive attacks by adherents to the ancient dogma) that "the right ventricle is made for the sake of the lungs, and for the transmission of the blood through them." In the first of several articles in this issue addressing pulmonary physiology and pathobiology, Husari et al. (5) report their observations on the effects of activated protein C administered during acute lung injury secondary to hypoxia. They show significant attenuation of lung injury, inflammation, leakage, and expression of cytokines, suggesting that it should be possible to test this hypothesis in the clinic. Cadirci et al. (6) studied the effects of administering α-lipoic acid, a mitochondrial coenzyme and antioxidant, to animals with acute lung injury from severe sepsis. They observed decreases in nuclear factor-κB activation and cytokine expression in lung tissues and increasing antioxidant capacity, leading to their proposal that randomized controlled clinical trials should be considered. Chapados et al. (7) evaluated the effect of hypoxia and reoxygenation with either 21% or 100% oxygen in newborn piglets subjected to 2 hours of normocapnic hypoxia. Piglets developed hypotension during reoxygenation, but they further observed high cortisol responses to corticotropin challenge in the 21% and sham groups, adding new information to the body of literature on the strategies for neonatal resuscitation.

In de Motu, Chapter XVI, "The Circulation Of The Blood Is Further Proved," Harvey considered the observations that contagions and "poisoned wounds" can spread to involve the whole body and "that the contagion impressed upon or deposited in a particular part, is by-and-by carried by the returning current of blood to the heart, and by that organ is sent to contaminate the whole body." The identity of causative agents underlying this "systemic contamination" was revealed during a span separated by 100 years: advances in the late 19th century, stated as the Germ Theory of Disease, implicated toxins derived from pathogens (e.g., endotoxins and enterotoxins), and advances in the late 20th century, stated as the Cytokine Theory of Disease, implicated toxins derived from the host (e.g., cytokines and damage-associated molecular pattern molecules; reviewed in Tacey [8]). A series of articles in this issue address the pathobiological effects of endogenous and exogenous mediators of shock and tissue injury. Chang et al. (9) studied shock caused by exposure to lipoteichoic acid, a component of gram-positive outer membranes that stimulate a damaging cytokine production by binding to TLR2 expressed on cytokine-producing cells of the innate immune system. Ketamine exposure to murine macrophage-like RAW cells significantly inhibited lipoteichoic acid-mediated tumor necrosis factor transcription and release, an observation that, they note, has potential implications for developing experimental therapeutics to prevent septic shock. Verma et al. (10) administered lipopolysaccharide to induce shock in mice and observed that administration of DNAzymes, divalent cation-dependent RNA phosphodiesterases that posttranscriptionally downregulate a targeted gene, in their case, inducible nitric oxide synthase. DNAzyme administration significantly inhibited cytokine expression and improved survival, leading the authors to suggest that this approach may be useful for the development of pharmacological agents. Suda et al. (11) studied severe sepsis induced by perforating the cecum and assessed the effects of administering sivelestat, an inhibitor of neutrophil elastase approved for clinical use in Asia for acute lung injury in patients. They observed that this agent significantly improved survival, reduced serum HMGB1 levels, and protected against pulmonary damage, leading them to advocate for future clinical trials in sepsis. Chen et al. (12) also studied lethal sepsis in the cecal perforation model to determine the basis of vascular hyporeactivity developing 18 hours after the onset of sepsis. They observed that exposure of the thoracic aorta to norepinephrine was associated with impaired handling of calcium and vascular hyporeactivity mediated in part by nitric oxide. Kawarabayashi et al. (13) administered Escherichia coli to rats that had been subjected to bile duct ligation 7 days earlier and observed overgrowth of bacteria in liver, decreased natural killer T cells, and suppressed interferon-γ. They conclude that decreased production of interferon-γ by liver mononuclear cells may contribute to reduced phagocytosis by Kupffer cells.

Years of dissection, observation, calculation, and experimentation enabled Harvey to mount a direct challenge to Galen, a figure held in God-like status. He "…began to think whether there might not be a Motion, As It Were, In A Circle. Now, this I afterwards found to be true; and I finally saw that the blood, forced by the action of the left ventricle into the arteries, was distributed to the body at large and its several parts…" Harvey assigned to the heart its proper role, as the organ that distributes "the blood in due proportion to the several parts of the body" in quantities necessary to meet the demands of the tissue. He also recognized that the heart was nourished by arterial supplies "…for its own especial behoof in its coronary veins and arteries." In this issue, Roesner et al. (14) studied myocardial ischemia in pigs and assessed the effects of administering a pharmacological inhibitor of poly(ADP-ribose)polymerase, a nuclear enzyme implicated in depleting NAD+ and increasing cytokine release. Inhibition of poly(ADP-ribose)polymerase with INO-1001 increased hemodynamic function assessed by stroke volume, cardiac index, and mixed venous oxygen saturation, suggesting that further study is warranted. Di Paola et al. (15) studied ischemia/reperfusion injury after occlusion of the superior mesenteric and celiac artery and observed that administration of the A2A receptor antagonist CGS 21680 significantly reduced intestinal neutrophil infiltration, apoptosis, P-selectin and intercellular adhesion molecule-1 expression, tissue injury, and survival. They propose the hypothesis that selective activation of A2A receptors may be a therapeutic strategy. Kerkweg et al. (16) used a model of severe muscle trauma to address whether the release of chelatable iron from this tissue constitutes an oxidative hazard. They observed that it did not promote systemic oxidative damage in this model, but that it catalyzed the formation of toxic hydroxyl radicals locally, which can worsen the severity of muscle destruction.

Harvey began his 17-chapter tome with a dedication letter to King Charles I, but he began Chapter I by noting that the onset of his vivisection studies was arduous, marked by overwhelming difficulties, to the point that he despaired that the answers to the mysteries he studied would remain known only to God. Years, and countless dissections and experiments later, he closed his treatise with words that ring true today, providing inspiration and encouragement to those seeking logic in the field of shock, indeed all of science; to individuals bent on revealing fundamental principals; and to those who experiment to discover new fonts of knowledge that can benefit humankind. "All these appearances, and many others, to be noted in the course of dissection, if rightly weighed, seem clearly to illustrate and fully to confirm the truth contended for throughout these pages, and at the same time to oppose the vulgar opinion; for it would be very difficult to explain in any other way to what purpose all is constructed and arranged as we have seen it to be."

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1. William H (1578-1657): On the Motion of the Heart and Blood in Animals, 1628. Robert Willis, trans. Scientific Papers; Physiology, Medicine, Surgery, Geology, With Introductions, Notes and Illustrations. New York, NY: PF Collier & Son [c1910]. The Harvard Classics v. 38.
2. Lee C-H, Wang J-Y, Wu Y-K, Chiu H-W, Lan C-C, Chang H, Chen C-Y: Pulse pressure power spectrum predicts volume responsiveness in shock patients without sedation. Shock 33:454-459, 2010.
3. Mittal A, Göke F, Flint R, Loveday BPT, Thompson N, Delahunt B, Kilmartin PA, Cooper GJS, MacDonald J, Hickey A, et al: The redox status of experimental hemorrhagic shock as measured by cyclic voltammetry. Shock 33:460-466, 2010.
4. Sharma P, Mongan PD: Hypertonic sodium pyruvate solution is more effective than Ringer's ethyl pyruvate in the treatment of hemorrhagic shock. Shock 33:532-540, 2010.
5. Husari AW, Khayat A, Awdeh H, Hatoum H, Nasser M, Mroueh SM, Zaatari G, El-Sabban M, Dbaido GS: Activated protein C attenuates acute lung injury and apoptosis in a hyperoxic animal model. Shock 33:467-472, 2010.
6. Cadirci E, Altunkaynak BZ, Halici Z, Odabasoglu F, Uyanik MH, Gundogdu C, Suleyman H, Halici M, Albayrak M, Unal B: α-Lipoic acid as a potential target for the treatment of lung injury caused by cecal ligation and puncture-induced sepsis model in rats. Shock 33:479-484, 2010.
7. Chapados I, Chik CL, Cheung P-Y: Plasma cortisol response to ACTH challenge in hypoxic newborn piglets resuscitated with 21% and 100% oxygen. Shock 33:519-525, 2010.
8. Tacey KJ: Physiology and immunology of the cholinergic anti-inflammatory pathway. J Clin Invest 117(2):289-296, 2007.
9. Chang H-C, Lin K-H, Tai Y-T, Chen J-T, Chen R-M: Lipoteichoic acid-induced TNF-α and IL-6 gene expressions and oxidative stress production in macrophages are suppressed by ketamine through downregulating toll-like receptor 2-mediated activation of ERK1/2 and NFκB. Shock 33:485-492, 2010.
10. Verma N, Tripathi SK, Chaudhury I, Das HR, Das RH: iNOS-targeted 10-23 DNAzyme reduces LPS-induced systemic inflammatory and mortality in mice. Shock 33:493-499, 2010.
11. Suda K, Takeuchi H, Hagiwara T, Miyasho T, Okamoto M, Kawasako K, Yamada S, Suganuma K, Wada N, Saikawa Y, et al: Neutrophil elastase inhibitor improves survival of rats with clinically relevant sepsis. Shock 33:526-531, 2010.
12. Chen S-J, Li S-Y, Shih C-C, Liao M-H, Wu C-C: NO contributes to abnormal vascular calcium regulation and reactivity induced by peritonitis-associated septic shock in rats. Shock 33:473-478, 2010.
13. Kawarabayashi N, Seki S, Hatsuse K, Kinoshita M, Takagawa T, Tsujimoto H, Kawabata T, Nakashima H, Shono S, Mochizuki H: Immunosuppression in the livers of mice with obstructive jaundice participates in their susceptibility to bacterial infection and tumor metastasis. Shock 33:500-506, 2010.
14. Roesner JP, Mersmann J, Bergt S, Bohnenberg K, Barthuber C, Szabo C, Nöldge-Schomburg GEF, Zacharowski K: Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size. Shock 33:507-512, 2010.
15. Di Paola R, Melani A, Esposito E, Mazzon E, Paterniti I, Bramanti P, Pedata F, Cuzzocrea S: Adenosine A2A receptor-selective stimulation reduces signaling pathways involved in the development of intestine ischemia and reperfusion injury. Shock 33:541-551, 2010.
16. Kerkweg U, Pamp K, Fieker K, Petrat F, Hider RC, de Groot H: Release of redox-active iron by muscle crush trauma: no liberation into the circulation. Shock 33:513-518, 2010.
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