*This is an article from the Winter 2022 issue of Contentment Magazine.
By Lewis Coleman, MD, FAIS
In my previous essays I have offered an abbreviated description of the mammalian stress mechanism. This essay describes the three activation pathways of the stress mechanism in greater detail, in preparation for an explanation of revolutionary advancements in disease treatments.
Normally the mammalian stress mechanism functions efficiently and unobtrusively to repair tissues and regulate organs, but excessive and unrelenting combinations of environmental stresses induce stress mechanism hyperactivity via its three synergistic pathways. This causes harmful stress mechanism hyperactivity that manifests as disease. Thus, stress mechanism hyperactivity is the universal cause of disease, and this explains the similar symptoms and close relationships of seemingly unrelated illnesses. All forms of disease threaten longevity by causing harmful stress mechanism hyperactivity that depletes and squanders stress mechanism substrates and produces excessive quantities and defective versions of its products that damage tissues and disrupt organs. The greater the severity of disease, and the longer it persists, the greater its threat to health and longevity.
To appreciate all this, one must understand how environmental stress factors activate the stress mechanism via its the three synergistic activation pathways. Each pathway responds to different types of environmental stress. The nociception pathway and the cognitive pathway are closely related nervous sensory pathways that activate blood enzyme factor VIII. The tissue disruption pathway is activated by tissue damage, which activates blood enzyme factor VII. The synergistic, independently fluctuating activities of the three pathways are altered by multiple factors, so that they produce confusing combinations of fluctuating disease manifestations that obscure the relative simplicity of the causative stress mechanism.
Figure 1. A diagram of the mammalian stress mechanism that illustrates its activation pathways. The cognitive pathway and the nociception pathway are portrayed on the left as elements of the Capillary Gate Component that activates factor VIII. The Tissue Repair Component and the Tissue Disruption Pathway are essentially the same and are portrayed in blue on the right. Tissue disruption exposes factor VII to tissue factor, which activates factor VII. The activity of each component exaggerates that of the other to generate “positive feedback” and focuses the powerful effects of the stress mechanism to repair tissues and regulate physiology.
The Nociception Pathway
The Nociception Pathway consists of nociceptors (tissue disruption sensors in skin and internal organs), peripheral sensory nerves, and specialized spinal cord nociception pathways. Nociceptors are subspecialized into mechanoreceptors that detect tissue distortion and damage; proprioceptors that detect position and movement; and chemoreceptors that detect hypercarbia, hypoxia, and acid levels. They generate nervous activity called “nociception” that travels via peripheral sensory nerves to specialized spinal cord nociception pathways. The spinal cord pathways simultaneously conduct nociception to the brain AND to sympathetic ganglia that lie outside the spinal cord in the in the chest and abdomen.
Nociceptors and autonomic innervation are not uniformly distributed. Nociceptors are present in skin and internal organs but are absent in the brain. Similarly, the lung, brain, and bowel are replete with autonomic ganglia and a fine mesh of autonomic (sympathetic and parasympathetic) nerve endings that are lacking in muscle, skin, and connective tissues. Thus, nociception and autonomic activity primarily affect internal organs.
The sympathetic ganglia generate sympathetic nervous activity that increases microvascular flow resistance in organs, which decreases organ perfusion and inhibits organ function. Inflammation exaggerates nociceptor sensitivity, which explains why damaged tissues are painful. In addition, the spinal cord nociception pathways exhibit “windup syndrome” so that persistent stimulation amplifies their activity.
The brain interprets nociception as pain, which exaggerates sympathetic tone and activity. Anesthesia prevents brain function that interprets nociception as pain, but anesthesia has negligible effect on the spinal cord or sympathetic ganglia. Thus, general anesthesia must be supplemented with analgesia (such as narcotics or nerve blocks) to prevent harmful surgical sympathetic hyperactivity transmitted via spinal pathways during surgery.
The brain inhibits spinal cord nociception pathways via “corticofugal” (descending) nervous activity from the brain to the spinal cord.1 This enables the brain to regulate pain perception in accord with environmental circumstances. The classical example is that of a soldier who is wounded during battle but continues to function effectively while remaining unaware of his injury. However, when the excitement of the battle subsides, he suddenly becomes aware of incapacitating pain caused by his injury. Anesthesia abolishes this corticofugal inhibition, which is another reason that analgesia is necessary to optimize surgical outcome during general anesthesia.
Another example that illustrates corticofugal inhibition is quadriplegia, which is caused by spinal cord injuries high in the neck that disrupt communications between the brain and the spinal cord, while the spinal cord continues to function normally below the level of the injury. The brain no longer receives nociception signals from the lower parts of the body, so the victim remains unaware of painful stimulation below his neck and shoulders. The spinal cord is freed from corticofugal inhibition, so that uninhibited spinal cord nociception pathways become hyperactive. This produces a dangerous condition called “autonomic hyperreflexia” wherein trivial stimulation of tissues in the lower body causes exaggerated sympathetic nervous activity that manifests as tachycardia, hypertension, and decreased organ perfusion.
Anesthesia and Nociception
Consciousness interprets nociception as pain. General anesthesia inhibits consciousness and extinguishes the perception of nociception as pain in a progressive fashion. This conveys the powerful but false impression that anesthesia has analgesic properties. On the contrary, anesthesia abolishes the descending inhibition of spinal cord nociception pathways, even as it extinguishes the ability to perceive nociception as pain. This has the effect of indirectly exaggerating harmful surgical sympathetic nervous hyperactivity that undermines organ perfusion and oxygenation. As a result, general anesthesia must be supplemented with analgesia (such as narcotics) to optimize surgical outcome.2
Analgesia and Nociception
Analgesia inhibits nociception. There are three classes of analgesic agents:
- Narcotics such as morphine inhibit spinal cord nociception pathways. They are virtually free of toxicity, but they inhibit respiratory nociceptors. However, hypercarbia counteracts narcotic respiratory depression and speeds narcotic metabolism and clearance.3-6
- Local analgesics such as lidocaine inhibit peripheral sensory nerves, spinal cord pathways, and nociceptors alike, depending on how and where they are administered. However, they are toxic and must be managed carefully.
- NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin and Tylenol directly inhibit peripheral nociceptors. These are even more toxic than local analgesics.
Parasympathetic Nervous Activity
Sympathetic nervous activity is generally opposed and counterbalanced by “parasympathetic” nervous activity that originates in the brainstem and is conducted to internal organs by the vagus nerve. Parasympathetic nervous activity releases nitric oxide (NO) from the vascular endothelium, which opens the capillary gate, reduces microvascular flow resistance, increases capillary flow, and promotes organ function. In the research literature this is called “Nitrergic Neurogenic Vasodilation.”
The Cognitive Pathway
The Cognitive Pathway is of particular interest to AIS members because it explains how emotional adversity harms health, which has previously remained mysterious. It consists of the cerebral cortex, which generates consciousness; a memory mechanism that records and retains an audiovisual record of all waking moments; a dreaming mechanism that evaluates the memory records during sleep to identify dangerous environmental circumstances; and an emotional mechanism that generates fear and anxiety when it detects dangerous circumstances identified during the dreaming process. These seemingly unrelated mechanisms function together as a mechanism of “fight or flight” that pre-emptively detects dangerous environmental circumstances and activates stress mechanism hyperactivity to facilitate survival in emergency situations.
Consciousness is generated by the cerebral cortex. It interprets nociception as pain, olfactory sensation as smell, optic sensation as sight, and auditory sensation as sound. It works with the memory mechanism to integrate all forms of sensory information into a unified perception of environmental surroundings.
The Memory Mechanism
The ability to retain vivid audiovisual memories, complete with associated emotions, of all waking moments was inadvertently discovered by Wilder Penfield, a neurosurgeon who stimulated various parts of the brain to identify the source of epilepsy.7 These memories ordinarily remain suppressed and subconscious, but in rare cases they invade awareness and cause “Hyperthymestic memory.” This was first documented in a woman named Jill Price, who sought the help of memory experts at UC Irvine because she was continually distracted by childhood memories that disrupted her ability to function.8,9 Some find this condition useful. For example, hyperthymestic memory enables the actress Marylou Henner to recall her acting scripts effortlessly. Mild forms of the condition explain “photographic memory” enjoyed by some students.
The Dreaming Mechanism
During Rapid Eye Movement (REM) sleep, a dreaming mechanism automatically reviews memory records to identify dangerous environmental circumstances. During this dreaming activity the brain automatically prevents skeletal muscle activity that would otherwise cause violent activity during sleep.10 This continual re-assessment of retained memory explains the phenomenon of “allostasis”—the ability of animals to gradually adapt their behavior to changing environmental circumstances.
The Emotional Mechanism
The emotional mechanism monitors consciousness and generates fear and anxiety when it detects dangerous environmental circumstances previously identified by the dreaming mechanism. This enables pre-emptive avoidance of environmental dangers. The fear and anxiety activate sympathetic nervous activity that releases HPA axis hormones (epinephrine, cortisol, glucagon, etc.) to facilitate pre-emptive “fight or flight.”
Fight or Flight
The fight or flight mechanism combines the mechanisms of consciousness, memory, dreaming, and emotion to avoid environmental dangers, and optimize survival in life-or-death situations such as attacks by a predator. However, its activity is inherently wasteful, harmful, and even life-threatening. It generates sympathetic nervous activity that releases HPA hormones, elevates blood sugar, increases blood coagulability, undermines organ perfusion and oxygenation, and consumes and wastes glucose, fibrinogen, ATP, and other body substrates.
The fight or flight mechanism is powerful and dangerous. Once activated, it can cause lingering emotional activity that is difficult to extinguish. Chronic fear and anxiety exaggerate sympathetic nervous activity, which increases capillary gate activity,11,12 accelerates capillary senescence, and generates abnormal amyloid protein that deposits in tissues and promotes inflammation and sclerosis, undermines function, manifests as chronic illnesses, and undermines life span. Severe, acute fear and terror can be lethal, as in uninjured persons caught near the epicenter of earthquakes who suffer sudden death. Survivors exhibit increased heart disease, blood enzyme elevations, increased blood coagulability, and reduced life span.13-20
The fight or flight mechanism explains numerous “neurotic” phenomena such as the “Stockholm Syndrome” seen in kidnap victims and PTSD (Post Traumatic Stress Syndrome) suffered by soldiers. Children are particularly vulnerable because they cannot defend themselves when they are subjected to incest or excessive punishment, and this causes narcissism, criminal behavior, drug addiction, chronic illness, and emotional problems later in life.
Anesthesia and Consciousness
Both volatile inhalation anesthetics and sedatives, including beverage alcohol, inhibit consciousness in a dose-related manner, and beneficially abolish fear and anxiety. 100 years ago, George Washington Crile proved that potent pre-medication prevents untoward fear of surgery and improves surgical outcome.21 Anesthesia undermines the ability to perceive nociception as pain even before it eliminates the ability to speak. This was commonly observed during the era of ether, and it conveyed the enduring assumption that inhalation anesthetics possess analgesic properties, which implies that inhibiting consciousness is the key to controlling nociception, pain, and surgical stress. However, such is not the case, because the spinal cord nociception pathways and sympathetic ganglia remain active despite the effects of anesthesia and sedation. Worse yet, anesthesia abolishes the corticofugal (descending) inhibition of spinal cord nociception pathways. This indirectly hyper-activates spinal cord nociception pathways, and exaggerates harmful sympathetic activity that undermines tissue perfusion, tissue oxygenation, and organ protection during surgery.
Worse yet, uninhibited surgical nociception causes patients to spontaneously hyperventilate and deplete their tissue reserves of carbon dioxide. This dangerously undermines respiratory drive, disrupts oxygen transport and delivery to tissues, invites infarction. It creates a condition that is analogous to “Ondine’s Curse” of Greek mythology, wherein the gods cursed Ondine with a condition that would cause her to die if she fell asleep. Similarly, CO2 depleted patients appear to breathe normally after they emerge from anesthesia, but they may stop breathing and die if they fall asleep for any reason before they have replenished their CO2 reserves. This often happens after recovering patients are treated with small doses of narcotics and sedatives that encourage sleep, so that the problem is typically attributed to “narcotic hypersensitivity.”22,23 This danger is further intensified in the presence of obstructive sleep apnea (OSA) and other obscure medical maladies, particularly when surgical patients are discharged home in the care of medically ignorant friends and family.
This problem of unexpected postoperative respiratory arrest and death is the first recognized safety issue of modern anesthesia. The phenomenon was famously investigated by Dr. Yandell Henderson, the Director of the Human Physiology Laboratory at Yale Medical School.24 Dr. Henderson correctly identified the problem and recommended that patients breathe a mixture of 5% carbon dioxide and 95% oxygen during anesthesia to prevent CO2 depletion. This not only eliminated the postoperative deaths, but also prevented unexplained intraoperative deaths.24 During the same era Dr. George Washington Crile discovered that morphine supplementation of general anesthesia improves surgical outcome, and that massive morphine treatments can cure life-threatening bacterial sepsis and peritonitis without the need for antibiotics.2 We can now appreciate that narcotics and hypercarbia go together like love and marriage during general anesthesia. Narcotic supplementation inhibits sympathetic hyperactivity, prevents hyperventilation that depletes CO2, and promotes organ perfusion and oxygenation during surgery.6 Hypercarbia counteracts narcotic respiratory depression, optimizes tissue oxygenation, accelerates narcotic metabolism and clearance, and protects postoperative respiratory drive.25, 26
Unfortunately, the story does not end here. Dr. Ralph Waters, the founder of the MD anesthesiology profession, sought to ruin the reputation of the nurse-anesthetists who dominated anesthesia service after WWI, so that he could supplant them with his anesthesiology graduates. To accomplish this, he outrageously characterized carbon dioxide as “toxic waste, like urine” that must be “rid from the body” using mechanical hyperventilation during anesthesia. He devised devious animal studies27 that confused asphyxiation with anesthesia and toxicity, and fabricated fictitious clinical reports to bolster his arguments.28, 29 Unfortunately, he was successful in these scandalous endeavors, and he established a hoax that has escaped the bounds of anesthesia and derailed medical progress ever since.25, 26
Sympathetic nervous activity releases von Willebrand Factor hormone from the vascular endothelium, which closes the capillary gate and restricts blood flow to organs and tissues.
Parasympathetic nervous activity releases nitric oxide hormone from the vascular endothelium to open the capillary gate, and increase blood flow to organs and tissues. Autonomic balance thus regulates organ perfusion, which determines organ function. Consciousness affects autonomic balance, but autonomic activity persists in its absence.
Epinephrine and Insulin
Epinephrine and Insulin are opposing hormones that extend autonomic balance to peripheral muscles and tissues, where direct autonomic innervation is lacking. Sympathetic activity releases epinephrine from the adrenal gland, and epinephrine releases von Willebrand Factor from the vascular endothelium to close the capillary gate. Parasympathetic nervous activity releases insulin from the pancreas, and insulin releases nitric oxide from the vascular endothelium to open the capillary gate.12
Brain tissue is replete with “support cells” called astrocytes that secrete TPA (tissue plasminogen activator) that maintains brain perfusion and oxygenation despite massive doses of epinephrine that are administered for cardiopulmonary resuscitation. Otherwise, severe sympathetic hyperactivity causes or contributes to harmful organ and tissue hypoxia.
The Tissue Disruption Pathway
The Tissue Disruption Pathway activates tissue repair. It consists of tissue factor in extravascular tissues, blood borne enzyme factors VII, VIII, IX, and X, and the vascular endothelium, which isolates tissue factor from the blood enzymes.
The vascular endothelium is “selectively permeable” so that it allows the slow “penetration” of blood enzyme factor VII into extravascular tissues, where tissue factor enables its enzymatic activity, which generates small amounts of thrombin to energize slow fibroblast collagen generation tissue that enables tissue maintenance throughout the body.
Capillary Gate Function
The vascular endothelium simultaneously allows the slow “escape” of tissue factor into flowing blood, where it activates factor VII. Since factor VII activity is essential for the activity of factors VIII, IX and X, this enables continuous low levels of blood enzyme activities necessary for capillary gate function, which regulates cardiac output, blood flow distribution, and organ function.
Tissue damage disrupts the vascular endothelium and exposes tissue factor to VII, which stabilizes factor VII and enables its enzymatic activity. Since the other enzymes remain inert in the absence of factor VII activity, the activation of factor VII acts as a trigger that initiates the enzymatic interaction of factors VII, VIII, IX, and X, and determines its magnitude and location. The resulting enzyme activity generates thrombin to energize the conversion of fibrinogen into insoluble fibrin that binds blood cells into a viscoelastic clot, which substitutes for the damaged vascular endothelium and re-isolates blood enzymes from the damaged tissues beneath its protective surface. The gigantic size of factor VIII prevents it from penetrating the viscoelastic clot, which automatically limits clot formation to the immediate vicinity of tissue damage and prevents dangerous systemic coagulation. The viscoelastic clot is “selectively permeable” so that it governs the access of blood enzymes to the damaged tissues, and thereby regulates thrombin generation in the damaged tissues to energize cellular repair activities and prevent excessive thrombin generation that threatens malignancy. Toxic substances can promote disease and malignancy by exaggerating the permeability of the vascular endothelium and the viscoelastic clot.
The vascular endothelium is specialized to serve the requirements of organs and tissues, as illustrated in figure 2.
Figure 2 The Vascular Endothelium is sub-specialized to serve the requirements of various organs and tissues. Its cells are joined tightly together in brain tissue, which explains the so-called “blood-brain barrier.” It is “sinusoid” in the liver to facilitate the absorption of lipoproteins and toxic substances.
By OpenStax College – Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013., CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=30148246
Radiation and toxic chemicals do not disrupt the vascular endothelium, but they increase its permeability, which allows the penetration of factors VII and X into irradiated tissues, where they generate thrombin that energizes inflammation that exaggerates nociceptor sensitivity, causing sunburn pain.
Like radiation, toxic chemicals alter the permeability of the vascular endothelium and allow leakage of tissue factor into systemic circulation, which exaggerates blood coagulability. They also directly disrupt cellular organ function.
Invasive bacteria that enter the bloodstream trigger the “complement cascade” enzymes that rapidly generate thrombin to energize immune activity to attack the bacteria. The elevated thrombin levels open gaps between the cells of the vascular endothelium, which increases its permeability and exaggerates the escape of tissue factor into systemic circulation. The tissue factor activates factor VII, causing “positive feedback” that dangerously exaggerates systemic inflammation and blood coagulability.
Tissues vulnerable to bleeding are rich in tissue factor, which is consistent with its role in hemostasis and tissue repair. These include brain, spinal cord, retina, nerves, autonomic ganglia, lung, gonads, cervix, placenta, amniotic fluid, epithelium, renal glomeruli, and fibroblasts.30 This explains why the lung and brain are “target organs” that are first to exhibit distress with the onset of critical illnesses including ARDS, MOFS, SIRS, and eclampsia, and why these same organs are vulnerable to both primary and metastatic malignancy. Brain trauma allows tissue factor to escape from the brain into systemic circulation, causing systemic inflammation and hypercoagulability. Smoking is especially dangerous because delicate lung tissue is replete with tissue factor.
In my future essays I will explain the nature and difference between chronic and critical illnesses, and how stress theory confers powerful new treatment strategies that promise cures for everything from cancer to the common cold. Knowledge is power. Those who wish to learn more about stress theory and its implications are encouraged to explore the author’s website www.stressmechanism.com, which offers free downloads of his published papers, and read his recently published book called “50 Years Lost in Medical Advance: The Discovery of Hans Selye’s Stress Mechanism” that is published by the American Institute of Stress.
1 Melzack, R. & Wall, P. D. Pain mechanisms: a new theory. Science 150, 971-979 (1965).
2 Crile GW, L. W. Anoci-association. (Saunders, 1914).
3 Forrest, W. H., Jr. & Bellville, J. W. The Effect of Sleep Plus Morphine on the Respiratory Response to Carbon Dioxide. Anesthesiology 25, 137-141 (1964).
4 Bellville, J. W., Howland, W. S., Seed, J. C. & Houde, R. W. The effect of sleep on the respiratory response to carbon dioxide. Anesthesiology 20, 628-634 (1959).
5 Ainslie, S. G., Eisele, J. H., Jr. & Corkill, G. Fentanyl concentrations in brain and serum during respiratory acid–base changes in the dog. Anesthesiology 51, 293-297 (1979).
6 Anand, K. J. & Maze, M. Fetuses, fentanyl, and the stress response: signals from the beginnings of pain? Anesthesiology 95, 823-825 (2001).
7 Penfield, W. Gordon Wilson Lecture, The Mechanism of Memory. Trans Am Clin Climatol Assoc 62, 165-169 (1950).
8 Price, J. The Woman Who Can’t Forget: The Extraordinary Story of Living with the Most Remarkable Memory Known to Science–A Memoir. (Free Press, a division of Simon and Schuster, 2008).
9 Parker, E. S., Cahill, L. & McGaugh, J. L. A case of unusual autobiographical remembering. Neurocase 12, 35-49 (2006).
10 Ingravallo, F. et al. Sleep-related violence and sexual behavior in sleep: a systematic review of medical-legal case reports. J Clin Sleep Med 10, 927-935, doi:10.5664/jcsm.3976 (2014).
11 Coleman, L. S. A capillary hemostasis mechanism regulated by sympathetic tone and activity via factor VIII or von Willebrand’s factor may function as a “capillary gate” and may explain angiodysplasia, angioneurotic edema, and variations in systemic vascular resistance. Med Hypotheses 66, 773-775, doi:10.1016/j.mehy.2005.10.022 (2006).
12 Coleman, L. S. A Stress Repair Mechanism that Maintains Vertebrate Structure during Stress. Cardiovasc Hematol Disord Drug Targets, doi:BSP/CHDDT/E-Pub/00015 [pii] (2010).
13 Matsuo, T., Suzuki, S., Kodama, K. & Kario, K. Hemostatic activation and cardiac events after the 1995 Hanshin-Awaji earthquake. Int J Hematol 67, 123-129 (1998).
14 Matsuo, T., Suzuki, S., Kario, K. & Kobayashi, H. [Acute myocardial infarction in the 1995 Hanshin-Awaji Earthquake]. Rinsho Byori Suppl 104, 133-141 (1997).
15 Matsuo, T., Kobayashi, H., Kario, K., Suzuki, S. & Matsuo, M. [Role of biochemical and fibrinolytic parameters on cardiac events associated with Hanshin-Awaji earthquake-induced stress]. Rinsho Byori 46, 593-598 (1998).
16 Kario, K., McEwen, B. S. & Pickering, T. G. Disasters and the heart: a review of the effects of earthquake-induced stress on cardiovascular disease. Hypertens Res 26, 355-367 (2003).
17 Kario, K., Matsuo, T., Kobayashi, H., Yamamoto, K. & Shimada, K. Earthquake-induced potentiation of acute risk factors in hypertensive elderly patients: possible triggering of cardiovascular events after a major earthquake. J Am Coll Cardiol 29, 926-933 (1997).
18 Kario, K. et al. Factor VII hyperactivity and endothelial cell damage are found in elderly hypertensives only when concomitant with microalbuminuria. Arterioscler Thromb Vasc Biol 16, 455-461 (1996).
19 Kario, K. et al. Earthquake-induced cardiovascular disease and related risk factors in focusing on the Great Hanshin-Awaji Earthquake. J Epidemiol 8, 131-139 (1998).
20 Kario, K. & Matsuo, T. Increased incidence of cardiovascular attacks in the epicenter just after the Hanshin-Awaji earthquake. Thromb Haemost 74, 1207 (1995).
22 Coleman, L. S. A call for standards on perioperative CO(2) regulation. Can J Anaesth, doi:10.1007/s12630-011-9469-7 (2011).
23 Coleman, L. S. in apsf Newsletter Vol. Winter 2009-2020 (Anesthesia Patient Safety Foundation, Administrator, Deanna Walker Anesthesia Patient Safety Foundation Building One, Suite Two 8007 South Meridian Street Indianapolis, IN 46217-2922 e-mail address: [email protected] FAX: (317) 888-1482, 2010).
24 Henderson, Y. Resuscitation with Carbon Dioxide. Science 83, 399-402, doi:10.1126/science.83.2157.399 (1936).
25 Coleman, L. S. Four Forgotten Giants of Anesthesia History. Journal of Anesthesia and Surgery 3, 1-17 (2015). <http://www.ommegaonline.org/article-details/Four-Forgotten-Giants-of-Anesthesia-History/468>.
26 Coleman, L. S. 30 Years Lost in Anesthesia Theory. Cardiovasc Hematol Agents Med Chem 10, 31-49, doi:CHAMC-EPUB-20120116-001 [pii] (2012).
27 Leake, C. D. W., R.M. The Anesthetic Properties of Carbon Dioxid. J. Pharmacol. Exp. Ther. 33 (1928, January).
28 Waters, R. M. Toxic Effects of Carbon Dioxide. J.A.M.A 100:519, 1933, 219-224 (1933).
29 Waters, R. M. Carbon Dioxide. Can Med Assoc J 38, 240-243 (1938).
30 Fleck, R. A., Rao, L. V., Rapaport, S. I. & Varki, N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res 59, 421-437 (1990).