Prevention and treatment of vasodilatory septic shock
Circulatory shock is a significant and sustained loss of effective blood and plasma volume to critical key organ regions of the body, which results in a regional low-flow state, eventuating in hypoperfusion of critical peripheral tissues and organs . This pathophysiological situation thus leads to deficits in transcapillary exchange and nutritive blood flows. Clinically, there are five major types of circulatory shock: hypovolemic, cardiogenic, anaphylactic, distributive, and septic [1-3].
Septic shock is often termed “a vasodilatory shock” and is a leading cause of morbidity and mortality in the USA and Europe [1-4]. Both septic and traumatic shock involve substantial fluid loss, exudation from the microcirculatory blood vessels, and increases in postcapillary permeability. Unless this situation is treated quickly, these events trigger the demise of the patient. Septic shock is often treated with catecholamines, inotropic agents, vasopressin, and corticosteroids to maintain arterial blood pressure, venous return, cardiac output, and distribution of blood to key peripheral tissues (i.e., brain, heart, and kidneys) [1-5]. Despite the use of these drugs, this often results in decreased cardiac output, intensified peripheral ischemia, and multiple organ failure, particularly of the heart, kidneys, lungs, and liver, followed by death. With the increased number of hospital-borne infections caused by “superbugs”, increased numbers of septic shock patients are becoming more and more prevalent.
A major concern in the septic shock patient are the pathological changes that rapidly take place in the postcapillary venules, tiny microscopic blood vessels usually only 20-40 um wide. Blood pools in these microscopic vessels due to loss of vasomotor tone, increased adherence of leukocytes, monocytes, and macrophages to the inner endothelial cells of the venules followed by release of numerous cytokines and chemokines, often leading to what is termed a “cytokine storm” [1,4,6-10]. These events give rise to a severe inflammatory component which leads to increasing morbidity and mortality. Unless these inflammatory reactions can be “curtailed very rapidly, the patient will not survive. Knowing these events, first-hand, through our studies, over a period of more than 50 years [1,10-20], we have been working on approaches to the “septic shock syndrome” that attack the problem from several points, namely:
- The design of new molecules that can pharmacologically manipulate the microvascular arterioles and muscular venules by promoting ceilings on vasoconstriction and restoring close-to-normal microvascular tone [10-27].
- The design of molecules that stimulate various arms of the mononuclear phagocytic system [6,10,16,24,27-38].
- Searching for molecules that stimulate the innate immune system to ameliorate/prevent the inflammatory responses [10,34,38-40].
- Searching for molecules that would reduce the need for large transfusions of blood, plasma, and fluids [41-44].
- Searching for molecules, in the body, that prevent, and stem super-imposed infections caused by “superbugs” found in many hospital environments [44-49].
- Searching for molecules that can accelerate wound healing, particularly at the microvascular level .
The “classical” studies of Elie Metchnikoff, in 1884, and Walter B. Canon in the 1920’s suggested that the body might produce its own powerful host-defense factor(s) to defend against infections and fluid loss [51,52]. Metchnikoff’s early studies  pointed to the important contributions of macrophages and phagocytic leukocytes to natural (innate) resistance against pathogenic bacteria and viruses.
Over the past decade, many hospitalized patients have died of common and once treatable bacterial diseases, such as pneumonia and blood (septic) or urinary tract infections [53-59]. Nowadays, it is difficult to undertake major surgical procedures or chemotherapy without antibiotics, as more and more patients die afterwards from infections resulting in septic shock. Gram-negative “superbugs” seem to be the major culprits in many of these septic shock patient deaths [53-59]. Gram-negative bacteria are more difficult to kill than gram-positive bacteria because they are protected by “double membranes”. So, to kill the gram-negative bacteria, most of the approaches have been to design antibiotics to penetrate these membrane barriers. In our opinion, another likely approach would be to engulf the bacteria and digest them within “supercharged” macrophages, Kupffer cels, phagocytic leukocytes, platelets and NK cells. But for this to occur, the microcirculation to key organs, namely the liver, spleen, and lungs must perforce have optimal capillary blood flows and distribution. In addition, any therapy should prevent release of cytokines and chemokines, thus preventing “cytokine and chemokine storms”. We, thus, believe an ideal drug (or therapeutic modality) needed to stem gram-negative infections and septic shock should be one that could stimulate multiple arms of the innate immune system coupled to modulation of key organ microcirculatory blood flows. To our knowledge, only HDFx appears to combine these qualities and demonstrate therapeutic attributes against several classes of bacterial “superbugs” [10,44-50]. The uniqueness of HDFx to accelerate wound healing  and promote tissue regeneration  should greatly aid treatment and recovery of patients characterized with septic shock. Its many anti-inflammatory benefits [10,44-50] should make it a required therapeutic modality in all high-risk surgical procedures.
It is our belief that all patients subjected to invasive surgical procedures (with a predilection to development of septic shock) or patients in shock should be administered protective doses of HDFx prior to and after lung, heart and brain surgeries, or prolonged hospital stays.
Some of the original work and ideas for the discovery of HDFx were carried out while the authors were on the faculties of New York University School of Medicine and The Albert Einstein College of Medicine. In addition, the original studies mentioned herein were supported, in part, by NIH Grants and unrestricted funds from several pharmaceutical companies (i.e., Sandoz Inc; The UpJohn Co.; CIBA GEIGY Corp; and Bayer Pharmaceuticals).
- Altura BM, Lefer AM, Schumer W (1983) Handbook of Shock and Trauma. Raven Press, New York, USA.
- Suteu I, Bandila T, Cafrira A, Bucur A, Candea V (1977) Shock: Pathology, Metabolism, Shock Cell Treatment. Abacus Press, UK.
- Baue AE (1990) Multiple Organ Failure. Patient Care and Prevention. Mosby Year Book, St Louis.
- Kumar V, Abbas AK, Aster JC (2015) Robbins and Cotran Pathologic Basis of Disease. 9th (edn). Elsevier Saunders, Philadelphia, USA pp: 131-133.
- Shoemaker WC, Ayres S, Grenvik A, Holbrook PR, Thompson WL (1989) Textbook of Critical Care, 2nd (edn). WB Saunders Co, Philadelphia, USA.
- Altura BM (1983) Endothelium, reticuloendothelial cells, and microvasxular integrity: roles in host defense. In: Handbook of Shock and Trauma. Raven Press, New York pp: 51-55.
- Hershey SG (1964) Shock. Little Brown and Co, Boston.
- Majno G, Joris I (2004) Cells, Tissues and Diseases. Oxford University Press, New York.
- Murphy K, Weaver C (2017) Janeway’s Immunology, 9th (edn). Garland Science, New York.
- Altura BM, Gebrewold A, Carella A, Altura BT (2016) HDFx: A novel immunomodulator for the amelioration of hypovolemic shock in the OR, cancer patients and on the battlefield. J Clin Med and Therap 1: e003.
- Altura BM, Hershey SG, Zweifach BW (1965) Effects of a synthetic analogue of vasopressin on vascular smooth muscle. Proc Soc Exp Biol Med 119: 258-261. [Crossref]
- Altura BM, Hsu R, Mazzia VDB, Hershey SG (1965) Influence of vasopressors on survival after traumatic, intestinal ischemic and endotoxin shock in rats. Proc Soc Exp Biol Med 119: 389-393. [Crossref]
- Altura BM, Hershey SG, Mazzia VD (1966) Microcirculatory approach to vasopressor therapy in intestinal ischemic (SMA) shock. Am J Surg 111: 186-192. [Crossref]
- Altura BM (1966) Differential actions of polypeptides and other drugs on coronary inflow vessels. Am Heart J 72: 709-711. [Crossref]
- Hershey SG, Altura BM (1967) Influence of vasoexcitor-pressor drugs on microvascular injury in shock. Bibl Anat 9: 33-37. [Crossref]
- Altura BM, Hershey SG (1967) Use of reticuloendothelial phagocytic function as an index in shock therapy. Bull N Y Acad Med 43: 259-266. [Crossref]
- Altura BM, Hershey SG (1967) Pharmacology of neurohypophyseal hormones and their synthetic analogues in the terminal vascular bed. Structure-activity relationships. Angiology 18:428-439. [Crossref]
- Altura BM, Hershey SG (1970) Microcirculatory actions of vasoactive polypeptides and their use in the treatment of experimental shock. Adv Exp Biol Med 21: 399-408.
- Altura BM (1970) Significance of amino acid residues in vasopressin on contraction in vascular muscle. Am J Physiol 219: 222-229. [Crossref]
- Altura BM, Hershey SG (1972) A structure-activity basis for vasotropic therapy in shock. Adv Exp Med Biol 21:399-408.
- Altura BM (1973) Selective microvascular constrictor actions of some neurohypophyseal peptides. Eur J Pharmacol 24: 49-60. [Crossref]
- Altura BM (1973) Significance of amino acid residues in position 8 of vasopressin on contraction in rat blood vessels. Proc Soc Exp Biol Med 142: 1104-1110. [Crossref]
- Altura BM (1975) Dose-response relationships for arginine vasopressin and synthetic analogs on three types of rat blood vessels: possible evidence for regional differences in vasopressin receptor sites within a mammal. J Pharmacol Exp Ther 193: 413-423.
- Altura BM (1976) DPAVP: a vasopressin analog with selective microvascular and RES actions for the treatment of circulatory shock in rats. Eur J Pharmacol 37: 155-167. [Crossref]
- Altura BM (1976) Microcirculatory approach to the treatment of circulatory shock with a new analog of vasopressin, (2-phenylalanine, 8-ornithine) vasopressin. J Pharmacol Exp Ther 198: 187-196. [Crossref]
- Altura BM (1978) Pharmacology of venular smooth muscle: new insights. Microvasc Res 16: 91-117. [Crossref]
- Altura BM, Altura BT (1984) Actions of vasopressin, oxytocin, and synthetic analogs on vascular smooth muscle. Federation Proc 43: 80-86. [Crossref]
- Hershey SG, Altura BM (1966) Effects of pretreatment with aggregate albumin on reticuloendothelial system activity and survival after experimental shock. Proc Soc Exp Biol Med 122: 1195-1199.
- Altura BM, Hershey SG (1968) RES phagocytic function in trauma and adaptation to experimental shock. Am J Physiol 215: 1414-1419. [Crossref]
- Hershey SG, Altura BM (1969) Function of the reticuloendothelial system in experimental shock and combined injury. Anesthesiology 30: 138-143. [Crossref]
- Altura BM, Hershey SG (1970) Effects of glycerol trioleate on the reticuloendothelial system and survival after experimental shock. J Pharmacol Exp Ther 175: 555-564. [Crossref]
- Altura BM, Hershey SG (1972) Sequential changes in reticuloendothelial system function after acute hemorrhage. Proc Soc Exp Biol Med 139: 935-939. [Crossref]
- Altura BM (1974) Hemorrhagic shock and reticuloendothelial system phagocytic function in pathogen-free animals. Circulatory Shock 1: 295-300.
- Altura BM (1976) Sex and estrogens in protection against circulatory stress reactions. Am J Physiol 231: 842-847. [Crossref]
- Altura BM (1980) Recent progress in patho-physiology of shock: reticuloendothelial and neuro-endocrine stimulation. Jap J Clin Anesth 4: 745-758.
- Altura BM (1980) Reticuloendothelial cells and host defense. Adv in Microcirculation 9: 252-294.
- Altura BM (1980) Reticuloendothelial system and neuro-endocrine stimulation in shock therapy. Adv Shock Res 3: 3-25. [Crossref]
- Altura BM (1985) Microcirculatory regulation and dysfunction: Relation to RES function and resistance to shock and trauma. In: The Reticuloendothelial System, Reichard SM, Filkins JP, eds. Plenum Press, New York.
- Altura BM, Altura BT (1974) Peripheral vascular actions of glucocorticoids and their relationship to protection in circulatory shock. J Pharmacol Exp Ther 190: 300-315. [Crossref]
- Altura BM (1975) Glucocorticoid -induced protection in circulatory shock: role of reticuloendothelial system function. Proc Soc Exp Biol Med 150: 202-206.
- Hershey SG, Altura BM (1966) Manipulation of the peripheral circulation with vasoactive drugs in the management of shock.: A microcirculatory approach. Schweiz Med Wschr 96: 1467-1471.
- Hershey SG, Altura BM (1973) Vasopressors in low-flow states. In: Pharmacology of Adjuvant Dugs 1st (edn). Clinical Anesthesia Series, Zauder HL, FA Davis Co, Philadelphia, USA pp: 31-76.
- Altura BM, Hershey SG (1972) Reticuloendothelial function in experimental injury and tolerance to shock. Adv Exp Med Biol 33: 545-569. [Crossref]
- Altura BM (1986) Endothelial and reticuloendothelial cell function: roles in injury and low-flow states. In: The Scientific Basis for The Care of the Critically Ill, Little RA, Frayn KN, eds. Manchester University Press, Manchester, UK pp: 259-274.
- Altura BM, Gebrewold A, Carella A (2009) A novel biologic immunomodulator, HDFx, protects against lethal hemorrhage, endotoxins and traumatic injury: potential relevance to emerging diseases. Int J Clin Exp Med 2:266-279. [Crossref]
- Altura BM (2016) HDFx: A novel immunomodulator and potential superbug super-warrior for hospitalized patients and battlefield casualties. Int J Vaccines and Research 3: 1-3.
- Altura BM, Gebrewold A, Carella A (2015) HDFx: A recently discovered biologic and its potential use in prevention and treatment of hemorrhagic fever viruses and antibiotic-resistant superbugs. J Hematol Thromboembolic Dis 4: 4.
- Altura BM, Altura BT (2017) HDFx: A novel biologic immunomodulator for potential control and treatment of NK Cell and macrophafe dysfunction in drug-resistant tuberculosis. Madridge J Immunol 1: 13-15.
- Altura BM, Gebrewold A, Carella A, Altura BT (2017) A novel immunomodulator and potential fighter against cytokine storms in inflammatory conditions in dogs and farm animals. Int J Vet Health Sci Res 5: 1-3.
- Altura BM, Carella A, Gebrewold A (2012) HDFx: a novel biologic immunomodulator accelerates wound healing and is suggestive of unique regenerative powers: potential implications for the warfighter and disaster victims. Int J Clin Exp Med 5: 289-295.
- Metchnikoff E (1884) Untersuchung ueber die intracellulare Verdauung beiwirbellosen Thieren. Arbeiten aus dem Zoologischen Institut zu Wien 5: 141-168.
- Canon WB (1939) The Wisdom of the Body, 2nd Edn. Oxford Univ Press, England.
- Gaynes R, Edwards JR; National Nosocomial Infections Surveillance System (2005) Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 41: 848-854. [Crossref]
- Blossom DR, McDonald LC (2007) The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis 45: 222-227.
- Burton DC, Edwards JR, Horan TC, Jernigan JA, Fridkin SK (2009) Methicillin –resistant Staphylococcus aureus central line-associated bloodstream infections in US intensive care units. JAMA 301: 727-736.
- Lee JH, Jeong SH, Cha SS, Lee SH (2009) New disturbing trend in antimicrobial resistance of gram-negative pathogens. PLoS Pathog 5: e1000221. [Crossref]
- Kuehn BM (2007) Antibiotic-resistant ‘Superbugs” may be trans mitted from animals to humans. JAMA 298: 2125-2126.
- Holden MT, Hauser H, Sanders M, Ngo TH, Cherevach I, et al. (2009) Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis. PLoS One 4: e6072. [Crossref]
- Marston HD, Dixon DM2, Knisely JM2, Palmore TN3, Fauci AS1 (2016) Antimicrobial Resistance. JAMA 316: 1193-1204. [Crossref]