Background on Sources, Symptoms, Biomarkers and Treatment of
Chronic Carbon Monoxide Poisoning

by Albert Donnay, MHS, Environmental Health Engineering
President, MCS Referral & Resource

"And have I not told you that what you mistake for madness is but overacuteness of the senses?"
Edgar Allan Poe, The Tell-Tale Heart, 1843

CO poisoning has long been known as the Great Imitator in medicine since its symptoms may mimic of those of many other disorders, including:

Alzheimer's · Addison's · Anemia · Asthma · Attention Deficit Disorder · Autism · Chronic Fatigue Syndrome · Depression · Dysautonomia · Fibromyalgia · Irritable Bowel Syndrome · Lupus (SLE) · Migraine · Multiple Chemical Sensitivity · Multiple Sclerosis · Neurally Mediated Hypotension · Panic Disorder · Parkinson's · Psychoses · Reactive Airways Dysfunction Syndrome · Reflex Sympathetic Dystrophy · Stress

Research into many of these disorders suggest that they may be caused by CO poisoning, and thus also possibly helped by CO treatments.

Sources of Carbon Monoxide (CO)
Symptoms of Chronic Low-Level CO Poisoning
Biomarkers of Chronic Low-Level CO Poisoning
Treatment of Chronic Low-Level CO Poisoning
References
Resources
Acknowledgements

Carbon monoxide is and has been the most common cause of both accidental toxic poisoning and death in the United States for over 100 years. This protocol is meant to assist physicians, respiratory therapists, and other medical professionals in diagnosing and treating cases of chronic low-level CO poisoning as defined by specific symptoms and objective biomarkers. It should not be used for self-diagnosis or self-treatment, or as a substitute for professional medical advice.
Note that pure oxygen can be obtained only by prescription except in the case of emergencies.

October 2006, 10th edition.
(c) 2000-2006 MCS Referral & Resources, 410-889-6666
Physician referrals and patient testimonials available upon request. Comments and suggestions are welcome.

1. SOURCES OF CARBON MONOXIDE

Exogenous Sources of Carbon Monoxide (from outside the body)

Carbon monoxide (CO) is produced from the incomplete combustion or burning of any fuel. Indoor exposures obviously are of greater concern than outdoor ones, as they are more likely to pose a risk to human health. The primary sources inside US homes and apartment buildings are smoking, unvented gas ranges and vehicles started in attached but unvented garages. Other CO sources include gas and oil furnaces, water and space heaters, ovens, wood and coal stoves, wood and coal fireplaces, gas-log inserts and explosives. Even electric ovens can produce CO when cooking some foods and always do so in self-cleaning mode when baking off spilled food.

The human body also breaks down some inhaled and ingested chemicals into CO, including ubiquitous dichloromethane (a common solvent especially in paint strippers and the most common propellant used in consumer product spray cans).

Since CO is odorless, colorless and tasteless, the only way to protect people from potentially fatal exposures is with a CO Detector, Monitor or CO Alarm (see Resources, below). While detectors and monitors can measure CO down to 1ppm (monitors do so continuously), CO alarms are barred by current UL and IAS standards from giving any digital readout below 30ppm or alarming below 70ppm. While there are no legal limits for indoor exposure, U.S. EPA regulations limit CO outdoors to an average 9 parts per million over 8 hours and 35 ppm maximum over 1 hour.

Endogenous Sources of Carbon Monoxide (from inside the body)

Stress of any kind induces increased production of heme oxygenase-1 (HO-1), the so-called "universal stress enzyme" found throughout the body, which breaks down heme from heme proteins into iron, biliverdin (which is then converted into bilirubin, a potent anti-oxidant), and carbon monoxide. The stresses that have been shown to induce HO-1 in animals and humans include heat, light, sound, odors, electromagnetic fields, infection, physical trauma and mental or psychological stress. Chronic stress in any of these pathways thus results in chronic destruction of heme and chronic low-level CO poisoning. The ability of so many different types of physical, biological, chemical and mental stressors to induce HO-1 explains why the core symptoms of chronic stress are so similar to CO poisoning regardless of the stressor (see Symptoms, below). Stress-induced HO-1 activity and the relatively constant activity of another isozyme, HO-2, that does not respond to stress, together account for about 75% of the human body's CO production. Other sources of CO include the auto-oxidation of phenols, flavenoids and halomethanes, the photo-oxidation of organic compounds, and the lipid peroxidation of membrane lipids.

HO activity can be directly measured in blood and various organs but of course varies widely, while endogenous CO levels, which also include any exogenous contribution, can be measured directly in breath, blood or muscle. The most commonly measured carboxyhemoglobin level (COHb) only identifies the percent of hemoglobin that is bound to CO, but this is normal in cases of chronic low-level CO poisoning, and even in acute cases not consistently related to symptoms.

2. SYMPTOMS OF CHRONIC LOW-LEVEL CARBON MONOXIDE POISONING

Whether arising from exogenous or endogenous sources, CO in the human body may be used or stored in several different ways until it is finally exhaled. CO binds much more aggressively than oxygen to all heme proteins, especially to hemoglobin (Hb). In doing so, it reduces the number of Hb binding sites available for carrying oxygen and makes the remaining oxygen bind more tightly. In muscle, CO binds more aggressively than oxygen to myoglobin (the main heme protein in muscle) and so interferes with oxygen use during exercise, especially in cardiac muscle.

CO activates guanylyl cyclase, which produces cyclic GMP, and nitric oxide synthase, which makes NO, but it also impairs mitochondrial energy metabolism and the function of cytochromes needed for detoxification. CO also triggers oxidative vascular stress (via endothelial cell production of NO and peroxynitrite) and brain lipid peroxidation. Most significantly, CO acts as a gaseous neurotransmitter in modulating many critical functions including respiration rate, heart rate, vasodilation, learning, memory and long-lasting adaptation to sensory stimuli (esp. odors).

Because chronic low-level CO poisoning impairs oxygenation of tissue, any organ may be affected, with the brain, heart and lungs being most sensitive to the effects of CO. The most common symptoms of chronic CO poisoning are actually the same as those of acute poisoning, except that they may vary considerably over time as they wax and wane in response to not just exogenous CO exposures but also in response to any chronically stressful stimuli, since all such stimuli induce HO-1 to breakdown heme proteins into CO (see Endogenous Sources, above).

10 Common Symptoms of Carbon Monoxide Poisoning

Headache
Fatigue, Weakness
Muscle Pain, Cramps
Nausea, Vomiting
Upset Stomach, Diarrhea
Confusion, Memory Loss
Dizziness, Incoordination
Chest Pain, Rapid Heartbeat
Difficult or Shallow Breathing
Changes in Sensitivity of Hearing, Vision, Smell, Taste or Touch

Because all these symptoms are common to so many disorders, no single one is considered diagnostic of CO poisoning, but CO should be suspected whenever a majority of these symptoms are reported together and no other cause is determinable, especially if the same symptoms are reported by more than one occupant of the enclosed space (building, vehicle, boat or plane).

A far more discriminating set of 30 symptoms appears in Edgar Allan Poe's classic 1839 tale, The Fall of The House of Usher, which we propose may be read as a literal description of chronic CO poisoning. Poe most likely suffered CO poisoning from his exposure to the coal gas that was used in the 1800s for indoor lighting. People with chronic CO poisoning today report having an average of 27 of these 30 symptoms in the last month, compared to healthy normal controls who average 2.

Edgar Allan Poe's 30 Chronic CO Symptoms

1. "ghastly pallor of the skin... a cadaverousness of complexion"

2. "miraculous lustre of the eye"

3. "gossamer texture" [of hair: soft,silky]

4. "nervous agitation"

5. "alternately vivacious and sullen"

6. "voiced varied from tremulous indecision to ..."

7. "...that species of energetic concision --abrupt, weighty, unhurried, and hollow-sounding enunciation--that leaden, self-balanced, and perfectly modulated guttural utterance, which may be observed in the lost drunkard"

8. "it was, he said, a constitutional and a family evil, and one for which he despaired to find a remedy--a mere nervous affection, he immediately added, which would soon pass off"

9. "it displayed itself in a host of unnatural sensations"

10. "he suffered much from a morbid acuteness of the senses"

11. "insipid food was alone endurable"

12. "could wear only garments of certain texture"

13. "the odors of all flowers were oppressive"

14. "eyes were tortured by even a faint light"

15. "there were but peculiar sounds, and these from stringed instruments, which did not inspire him with horror"

16. "phantasmagoric conceptions ... wild fantasies"

17. "fear"

18. "without having noticed my presence" [oblivious to comings and goings of others]

19. "he arrested and overawed attention ... an intensity of intolerable awe"

20. "radiation of gloom"

21. "painted an idea...pure abstractions"

22. "intense mental collectedness and concentration ...observable only in particular moments"

23. "roamed from chamber to chamber with hurried, unequal, and objectless step"

24. "sleep came not near my couch"

25. "gazing upon vacancy for long hours, in an attitude of the profoundest attention, as if listening to some imaginary sound"

26. "hysteria in his whole demeanor"

27. "struggled to reason off the nervousness which had dominion over me"

28. "irrepressible tremor gradually pervaded my frame"

29. "there sat upon my heart an incubus of utterly causeless alarm"

30. "overpowered by an intense sentiment of horror, unaccountable yet unendurable"

3. BIOMARKERS OF CHRONIC LOW-LEVEL CARBON MONOXIDE POISONING

There are several biomarkers capable of identifying the impaired oxygen delivery associated with CO exposure and tracking its response to 100% oxygen treatment. Qualitatively, a SPECT scan of the brain shows the most dramatic evidence of decreased blood flow in various areas of the brain that all improve with oxygen treatment. Unfortunately, high-resolution 3-camera SPECT scans are hard to find and expensive, with scans costing thousands of dollars each and most health insurers unwilling to pay for them.

Quantitatively, and much less expensively (for just $50 to $100), one can order standard arterial and venous blood gases to compare the partial pressure of oxygen in venous blood (PvO2) with that of oxygen in arterial blood (PaO2). PaO2 is usually normal or low-normal in cases of CO poisoning but PvO2 is abnormally high, indicating substantial impairment of oxygen delivery from arterial blood plasma into tissue. Venous blood for the PvO2 analysis should be drawn at the elbow without a tourniquet. The optimum PvO2 level in healthy non-smoking adults is about 25mm Hg, while levels in CO poisoning (and CFS/FMS/MCS) patients are commonly in the range of 30 to 50. The optimum atereo-venous gap is 70 to 60mmHg: a smaller P(a-v)O2 gap is clear evidence that oxygen delivery to tissues and/or its uptake is impaired.

For screening adults, the fastest, least invasive and least expensive biomarker to assess is the concentration (in ppm) of CO in exhaled breath, which measures the total rate of CO excretion from all sources and correlates closely with COHb in healthy controls. This is commonly measured in smoking cessation clinics and some emergency rooms using handheld, battery powered, electro-chemical CO sensors with digital readouts designed for this purpose (see Resources, below). Because a 23-second breath hold is optimal (to allow time for CO exchange in the lungs), this test is not easily done by young children or people with significant respiratory impairments. In normal healthy adults, breathCO levels range from 0- 6ppm, while smokers range from 7ppm (after 24 abstinence) to over 70ppm (immediately after smoking). Elevated levels may be due to exogenous CO poisoning but are also associated with a variety of chronic diseases, including asthma, bronchitis, cystic fibrosis and diabetes. The amount of CO exhaled also increases when breathing enriched oxygen, so recording this immediately before and after 100% oxygen treatment provides a simple way to quantify the impact of each session on CO elimination.

Most commonly measured but least helpful is the carboxyhemoglobin level that gives the percent of hemoglobin (Hb) binding sites occupied by CO, arterial and venous COHb are the same because CO binds so tightly to Hb). The CO bound to Hb is much less active biologically than the CO that is less tightly bound to other heme proteins such as myoglobin and cytochromes or that circulating freely in blood plasma. Although COHb is usually significantly elevated in the hours immediately following an acute high level CO exposure--with minor symptoms starting around 10% COHb according to most textbooks–it usually normalizes within a few days of exposure (if not fatal) because the biological half life of COHb is only 4 to 6 hours. COHb levels measured weeks and months after a single acute CO exposure are usually normal (under 2% for non-smokers, under 10% for smokers) and rarely correlate with any residual chronic symptoms. So while a high COHb level confirms significant exposure to one or more sources of CO, a normal value cannot rule out chronic low-level exposure. The symptoms in chronic cases are more likely due to the myriad effects of CO in other more biologically active pathways (binding with cytochromes, for example) than to its interference with oxygen-binding on hemoglobin.

COHb can adjust to great variation in CO exposure and oxygen demand, although it may take weeks to habituate to new conditions. This is evident in how long it takes non-smoking coast dwellers to habituate to the lower oxygen pressures found at high altitudes compared to smokers, whose higher COHb levels are more like those of people who live at high altitude year round and who are more aerobically fit in such low-oxygen environments than visitors with lower COHb levels.

4. TREATMENT OF CHRONIC LOW-LEVEL CARBON MONOXIDE POISONING

For the treatment of chronic low-level CO poisoning evidenced by high PvO2 (regardless of COHb level), MCS Referral & Resources recommends Extended Normobaric Oxygen Therapy (ENOT). Three to four months of daily 2-hour sessions breathing 100% oxygen from a tank or concentrator while supine via a nasal canulus at 6 to 10 liters per minute are usually sufficient to normalize PvO2 and obtain lasting relief from the most common symptoms of chronic CO poisoning. ENOT is less expensive and more widely available than hyperbaric oxygen, which is the recommended treatment for acute CO cases (for information on this option, contact the Undersea & Hyperbaric Medicine Society, 301-942-2980). ENOT has fewer risks of adverse side effects than hyperbaric therapy and may be carried on by the patient at home after training by a respiratory therapist. Both Medicare and private insurers are usually willing to pay for home delivery of supplemental oxygen regardless of the source (compressed O2, liquid O2 or concentrator O2) as long as the need is documented and consistent with a diagnosis of CO poisoning. This protocol has not been evaluated in children (whose normal PvO2 range is unknown) but they clearly are more sensitive to both CO and 100% oxygen.

ENOT Indications

This protocol was developed for treating adults with at least 5 of the 10 most common symptoms of CO poisoning listed above (usually including chronic fatigue, sensory changes and cognitive dysfunction) who also have an abnormally elevated partial pressure of oxygen in venous blood. When drawn from the antecubital fossa without a tourniquet, the optimal PvO2 in healthy controls is about 25mmHg, so any PvO2 over 30, or a P(a-v)O2 gap of less than 60, may be considered abnormal. These admittedly arbitrary cutoffs are primarily for research purposes, however, and need not be strictly followed in clinical practice, where physicians may want to consider other factors in assessing the potential risks vs. benefits of oxygen treatment. Since PaO2 is rarely significantly decreased in CO cases and more painful to obtain than venous samples, arterial testing may be omitted unless documentation of the arterial-venous oxygen gap is needed.

Regardless of the initial PvO2 level, this should be rechecked weekly or biweekly during treatment. Daily oxygen should continue until PvO2 either falls below normal (25mmHg) and stays there or stops falling for two successive measurements. Of course, if a patient is still reporting subjective improvements at this point without adverse side effects, the treatments may be continued until the patient no longer reports any additional benefit or need. While no long-term studies have yet been done, anecdotal reports suggest PvO2 levels remain in the normal range and substantial symptom relief persists for months with no need for further daily oxygen treatment. However, physicians should consider prescribing a continuing supply of oxygen for use as needed to relieve symptoms of any new CO exposures (most insurance covers oxygen "as needed" for migraine if not for CO).

ENOT Contraindications

Extended normobaric oxygen therapy should not be attempted in anyone who has reacted poorly to 100% oxygen in the past. When first trying 100% oxygen, patients should be monitored closely by their physician for sudden or dramatic changes in heart rate, respiration, blood pressure and any reports of adverse effects associated with oxygen toxicity (especially any respiratory, neurologic or sensory complaints). If no adverse reactions are noted, patients may be taught how to continue daily treatments at home on their own, with a warning that they should immediately discontinue treatment and notify their physician if they notice any poorly-tolerated effects.

Medications, Supplements and Diet

Although no medications are needed to supplement extended normobaric oxygen therapy, the treatment theoretically works best if the patient's exposures to CO are minimized. This requires reducing exposures not just to exogenous CO but also to all the many types of physical, biological, chemical and mental stresses that increase endogenous CO production (via stress-induced HO-1 catabolism of heme). Since medications and supplements are a source of chemical stress and poorly tolerated by most people with chronic CO poisoning and related syndromes (Autism, ADHD, CFS, FMS, MCS etc), the protocol urges doctors to consider weaning their patients off all non-essential supplements and medications prior to starting ENOT (including anti-depressants except in potentially suicidal cases). While many of these patients have significant deficiencies in vitamins (particularly the B series), minerals (particularly magnesium and zinc) and hormones (particularly thyroid), we recommend testing for but not treating these deficiencies until PvO2 has been normalized and the oxygen therapy concluded, as some may self-correct with the improved oxygenation of tissue that ENOT provides. The only exception is for buffered vitamin C or some other buffered anti-oxidant which should be taken daily during oxygen treatment to boost the body's ability to deal with the free radicals formed by oxidative metabolism.

Low plasma volume should be treated concurrently with high water consumption (at least one glass per hour except when sleeping). Since chlorinated water, alcohol, caffeine and processed foods are all common sources of chemical stress in these patients, they should be avoided as much as possible during the oxygen treatment. If food intolerances have not already been identified and eliminated, this should be done with a rotation diet prior to starting ENOT. After their PvO2 normalizes, patients may try reintroducing a broader range of foods one at a time.

5. REFERENCES

Although prompt 100% oxygen has long been the standard therapy for the treatment of acute CO poisoning (within hours or day of exposure), there are no published studies on its extended use for the treatment of chronic CO symptoms as described in this protocol. The references cited below address the biological activity of CO, its role in sensory signaling, sensitization, and adaptation, the clinical features of chronic CO poisoning, biomarkers of CO poisoning, and oxygen treatment. They offer support for the protocol's working hypothesis, which is that anyone with CO symptoms and impaired oxygen delivery (as shown by high PvO2) may benefit from 100% oxygen therapy.

RE: Biological Activity of Carbon Monoxide from Endogenous and/or Exogenous Sources

Abraham, N.G., Drummond, G.S., Lutton, J.D., Kappas, A. The biological significance and physiological role of heme oxygenase. Cell Physiol Biochem, 1996, 6:129-168.
Acevedo CH, Ahmed A. Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy. J Clin Invest. 1998;101:949-55.
Amitai, Y., Zlotogorsk, Z., Golan-Katzav, V., Wexler, A., and Gross, D. Neuropsychological impairment from acute low-level exposure to carbon monoxide. Arch Neurol 1998; 55:845-848.
Arias-Diaz J, Villa N, Hernandez J, Vara E, Balibrea JL. Carbon monoxide contributes to the cytokine-induced inhibition of surfactant synthesis by human type II pneumocytes. Arch Surg. 1997;132:1352-60.
Ariyoshi T, Shiiba S, Hasegawa H, Arizono K. Effects of the environmental pollutants on heme oxygenase activity and cytochrome P-450 content in fish. Bull Environ Contam Toxicol. 1990;44:189-96.
Astrup, P. Intraerythrocytic 2,3-diphosphoglycerate and CO exposure. J. Appl. Physiol, 1976;41:893
Bauer M, Pannen BH, Bauer I, et al. Evidence for a functional link between stress response and vascular control in hepatic portal circulation. Am J Physiol. 1996;271:G929-G935
Brann DW, Bhat GK, Lamar CA, Mahesh VB. Gaseous transmitters and neuroendocrine regulation. Neuroendocrinology. 1997;65:385-95.
Brouillard RP, Conrad ME, Bensinger TA. Effect of blood in the gut on measurements of endogenous carbon monoxide production. Blood. 1975;45:67-9.
Burnett AL, Johns DG, Kriegsfeld LJ, et al. Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med. 1998;4:84-7.
Canning BJ, Fischer A. Localization of heme oxygenase-2 immunoreactivity to parasympathetic ganglia of human and guinea-pig airways. Am J Respir Cell Mol.Biol. 1998;18:279-85.
Christodoulides N, Durante W, Kroll MH, Schafer AI. Vascular smooth muscle cell heme oxygenases generate guanylyl cyclase- stimulatory carbon monoxide. Circulation. 1995;91:2306-9.
Clark JE, Green CJ, Motterlini R. Involvement of the heme oxygenase-carbon monoxide pathway in keratinocyte proliferation. Biochem.Biophys.Res Commun. 1997;241:215-20.
Coceani F, Kelsey L, Seidlitz E, et al. Carbon monoxide formation in the ductus arteriosus in the lamb: implications for the regulation of muscle tone. Br J Pharmacol. 1997;120:599-608.
Collman JP, Brauman JI, Doxsee KM. Carbon monoxide binding to iron porphyrins. Proc Natl Acad Sci U.S A. 1979;76:6035-9.
Cook MN, Nakatsu K, Marks GS, et al. Heme oxygenase activity in the adult rat aorta and liver as measured by carbon monoxide formation. Can J Physiol Pharmacol. 1995;73:515-8.
Cook MN, Marks GS, Vreman HJ, Nakatsu K, Stevenson DK, Brien JF. Ontogeny of heme oxygenase activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig. Brain Res Dev.Brain Res. 1996;92:18-23.
Cook MN, Marks GS, Vreman HJ, et al. Carbon monoxide formation in the guinea pig hippocampus: ontogeny and effect of in vitro ethanol exposure. Brain Res Dev.Brain Res. 1997;101:283-6.
Downard PJ, Wilson MA, Spain DA, Matheson PJ, Siow Y, Garrison RN. Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. J Surg Res. 1997;71:7-12.
Durante, W., Schafer, A.I. Carbon monoxide and vascular cell function. Int J Mol.Med, 1998, 2:255-262.
Estabrook RW, Franklin MR, Hildebrandt AG. Factors influencing the inhibitory effect of carbon monoxide on cytochrome P-450-catalyzed mixed oxidation reactions. Ann NY Acad Sci 1970;174:218-232.
Ewing JF, Maines MD. Glutathione depletion induces heme oxygenase-1 (HSP32) mRNA and protein in rat brain. J Neurochem. 1993;60:1512-9
Ewing JF, Maines MD. Distribution of constitutive (HO-2) and heat-inducible (HO-1) heme oxygenase isozymes in rat testes: HO-2 displays stage-specific expression in germ cells. Endocrinology. 1995;136:2294-302.
Ewing JF, Maines MD. Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. Brain Res Brain Res Protoc. 1997;1:165-74.
Farrugia G, Miller SM, Rich A, et al. Distribution of heme oxygenase and effects of exogenous carbon monoxide in canine jejunum. Am J Physiol. 1998;274:G350-G358
Fin C, da Cunha C, Bromberg E, et al. Experiments suggesting a role for nitric oxide in the hippocampus in memory processes. Neurobiol Learn.Mem. 1995;63:113-5.
Glabe A, Chung Y, Xu D, and Jue T. Carbon monoxide inhibition of regulatory pathways in myocardium. Am J Physiol. 1998;274:H2143-H2151.
Hedlund P, Ekstrom P, Larsson B, Alm P, Andersson KE. Heme oxygenase and NO-synthase in the human prostate--relation to adrenergic, cholinergic and peptide-containing nerves. J Auton.Nerv Syst. 1997;63:115-26.
Henningsson R, Alm P, Ekstrom P, Lundquist I. Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. Diabetes. 1999;48:66-76.
Ho KM, Ny L, McMurray G, Andersson KE, Brading AF, Noble JG. Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the huma urethral sphincter. J Urol. 1999;161:1968-72.
Horvath I, Loukides S, Wodehouse T, Kharitonov SA, Cole PJ, Barnes PJ. Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress. Thorax. 1998;53:867-70.
Hu Y, Yang M, Ma N, Shinohara H, Semba R. Contribution of carbon monoxide-producing cells in the gastric mucosa of rat and monkey. Histochem.Cell Biol. 1998;109:369-73.
Iselin CE, Ny L, Larsson B, et al. The nitric oxide synthase/nitric oxide and heme oxygenase/carbon monoxide pathways in the human ureter. Eur Urol. 1998;33:214-21.
Johnson RA, Colombari E, Colombari DS, Lavesa M, Talman WT, Nasjletti A. Role of endogenous carbon monoxide in central regulation of arterial pressure. Hypertension. 1997;30:962-7
Johnson RA, Kozma F, Colombari E. Carbon monoxide: from toxin to endogenous modulator of cardiovascular functions. Braz.J Med Biol Res. 1999;32:1-14.
Kostoglou-Athanassiou I, Forsling ML, Navarra P, Grossman AB. Oxytocin release is inhibited by the generation of carbon monoxide from the rat hypothalamus--further evidence for carbon monoxide as a neuromodulator. Brain Res Mol.Brain Res. 1996;42:301-6
Kostoglou-Athanassiou I, Costa A, Navarra P, Nappi G, Forsling ML, Grossman AB. Endotoxin stimulates an endogenous pathway regulating corticotropin- releasing hormone and vasopressin release involving the generation of nitric oxide and carbon monoxide. J Neuroimmunol. 1998;86:104-9.
Kozma F, Johnson RA, Zhang F, Yu C, Tong X, Nasjletti A. Contribution of endogenous carbon monoxide to regulation of diameter in resistance vessels. Am J Physiol. 1999;276:R1087-R1094.
Kutty RK, Kutty G, Rodriguez IR, Chader GJ, Wiggert B. Chromosomal localization of the human heme oxygenase genes: heme oxygenase-1 (HMOX1) maps to chromosome 22q12 and heme oxygenase-2 (HMOX2) maps to chromosome 16p13.3. Genomics. 1994;20:513-6.
Lamar CA, Mahesh VB, Brann DW. Regulation of gonadotrophin-releasing hormone (GnRH) secretion by heme molecules: a regulatory role for carbon monoxide? Endocrinology. 1996;137:790-3.
Maines M. CO: an emerging regulator of cGMP in the brain. Mol. Cell .Neurosci. 1993;4:389-397
Maines M. Carbon monoxide and nitric oxide homology: differential modulation of heme oxygenases in brain and detection of protein and activity. Methods Enzymol. 1996;268:473-88:473-88.
Maines MD, Abrahamsson PA. Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution. Urology. 1996;47:727-33.
Maines MD, Ewing JF. Stress response of the rat testis: in situ hydridization and immunohistochemical analysis of heme oxygenase-1 (HSP32) induction by hyperthermia. Biol Reprod. 1996;54:1070-9.
Maines M, Polevoda B, Coban T, et al. Neuronal overexpression of heme oxygenase-1 correlates with an attenuated exploratory behavior and causes an increase in neuronal NADPH diaphorase staining. J Neurochem. 1998;70:2057-69.
Mancuso C, Preziosi P, Grossman AB, and Navarra P. The role of carbon monoxide in the regulation of neuroendocrine function. Neuroimmunomodulation. 1997;4:225-9.
Mancuso C, Tringali G, Grossman A, Preziosi P, Navarra P. The generation of nitric oxide and CO produces opposite effects on the release of immunoreactive interleukin-1beta from the rat hypothalamus in vitro: evidence for the involvement of different signaling pathways. Endocrinology. 1998;139:1031-7.
Mancuso C, Ragazzoni E, Tringali G, et al. Inhibition of heme oxygenase in the central nervous system potentiates endotoxin-induced vasopressin release in the rat. J Neuroimmunol. 1999;99:189-94.
Marks GS, Nakatsu K, Brien JF. Does endogenous zinc protoporphyrin modulate carbon monoxide formation from heme? Implications for long-term potentiation, memory, and cognitive function. Can J Physiol Pharmacol. 1993;71:753-4.
Marks GS. Heme oxygenase: the physiological role of one of its metabolites, carbon monoxide and interactions with zinc protoporphyrin, cobalt protoporphyrin and other metalloporphyrins. Cell Mol.Biol (Noisy.-le.-grand.). 1994;40:863-70.
Marks GS, McLaughlin BE, Vreman HJ, et al. Heme oxygenase activity and immunohistochemical localization in bovine pulmonary artery and vein. J Cardiovasc.Pharmacol. 1997;30:1-6.
Maulik N, Engelman DT, Watanabe M, et al. Nitric oxide/carbon monoxide. A molecular switch for myocardial preservation during ischemia. Circulation. 1996;94:II398-II406
Meyer J, Prien T, Van Aken H, et al. Arterio-venous carboxyhemoglobin difference suggests carbon monoxide production by human lungs. Biochem.Biophys.Res Commun. 1998;244:230-2.
Montecot C, Seylaz J, Pinard E. Carbon monoxide regulates cerebral blood flow in epileptic seizures but not in hypercapnia. Neuroreport. 1998;9:2341-6.
Morita T, Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. J Clin Invest. 1995;96:2676-82.
Mirabella C, Ndisang JF, Berni LA, Gai P, Masini E, Mannaioni PF. Modulation of the immunological activation of human basophils by carbon monoxide. Inflamm Res. 1999;48 Suppl 1:S11-2:S11-S12
Miro O, Casademont J, Barrientos A, Urbano-Marquez A, and Cardellach F. Mitochondrial cytochrome c oxidase inhibition during acute carbon monoxide poisoning. Pharmacol Toxicol. 1998;82:199-202.
Murphy BJ, Laderoute KR, Vreman HJ, et al. Enhancement of heme oxygenase expression and activity in A431 squamous carcinoma multicellular tumor spheroids. Cancer Res. 1993;53:2700-3.
Nathanson JA, Scavone C, Scanlon C and McKee M. The cellular Na+ pump as a site of action for CO and glutamate: a mechanism for long-term modulation of cellular activity. Neuron 1995;14:81-794.
Ndisang JF, Gai P, Berni L, et al. Modulation of the immunological response of guinea pig mast cells by carbon monoxide. Immunopharmacology. 1999;43:65-73.
Ny L, Alm P, Ekstrom P, Larsson B, Grundemar L, Andersson KE. Localization and activity of haem oxygenase and functional effects of carbon monoxide in the feline lower oesophageal sphincter. Br J Pharmacol. 1996;118:392-9.
Otterbein LE, Mantell LL, Choi AM. Carbon monoxide provides protection against hyperoxic lung injury. Am J Physiol. 1999;276:L688-L694
Overholt JL, Bright GR, Prabhakar NR. Carbon monoxide and carotid body chemoreception. Adv.Exp Med Biol. 1996;410:341-4:341-4.
Penney DG, Howley JW. Is there a connection between carbon monoxide exposure and hypertension? Environ Health Perspect. 1991;95:191-8:191-8. [found connection only with hypotension]
Piantadosi CA, Zhang J, Levin ED, Folz RJ, Schmechel DE. Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat. Exp Neurol. 1997;147:103-14
Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U.S A. 1997;94:10925-30.
Pozzoli G, Mancuso C, Mirtella A, Preziosi P, Grossman AB, Navarra P. Carbon monoxide as a novel neuroendocrine modulator: inhibition of stimulated corticotropin-releasing hormone release from acute rat hypothalamic explants. Endocrinology. 1994;135:2314-7.
Prabhakar NR, Dinerman JL, Agani FH, Snyder SH. Carbon monoxide: a role in carotid body chemoreception. Proc Natl Acad Sci U.S A. 1995;92:1994-7.
Prabhakar NR. Endogenous carbon monoxide in control of respiration. Respir Physiol. 1998;114:57-64.
Rodgers, P.A., Vreman, H.J., Dennery, P.A., and Stevenson, D.K. Sources of carbon monoxide in biological systems and applications of CO detection technologies. Semin Perinatol. 1994, 18:2-10.
Shinomura T, Nakao S, Mori K. Reduction of depolarization-induced glutamate release by heme oxygenase inhibitor: possible role of CO in synaptic transmission. Neurosci Lett. 1994;166:131-4.
Suematsu M, Wakabayashi Y, Ishimura Y. Gaseous monoxides: a new class of microvascular regulator in the liver. Cardiovasc.Res. 1996;32:679-86.
Stathers GM, Haeger-Aronsen B, Johsson G, Marcic L. CO in porphyria. Lancet. 1968;1:1204
Steiner AA, Colombari E, Branco LG. Carbon monoxide as a novel mediator of the febrile response in the central nervous system. Am J Physiol. 1999;277:R499-R507
Takahashi K, Nakayama M, Takeda K, Fujia H, Shibahara S. Suppression of heme oxygenase-1 mRNA expression by interferon-gamma in human glioblastoma cells. J Neurochem. 1999;72:2356-61.
Thom, S.R. CO-mediated brain lipid peroxidation in the rat brain. J Appl Physiol 1990;68-997-1003.
Thom SR, Kang M, Fisher D and Ischiropoulos H. Release of glutathione from erythrocytes and other markers of oxidative stress in carbon monoxide poisoning. J Appl Physiol 1997 May;82(5):1424-32
Thom, S.R, Xu, Y.A.,and Ischiropoulos, H. Vascular endothelial cells generate peroxynitrite in response to carbon monoxide exposure. Chem Res Toxicol 1997; 10:1023-1031.
Thom, S.R, Ohnishi, S.T., Fisher, D., Xu, Y.A., and Ischiropoulos, H. Pulmonary vascular stress from carbon monoxide. Toxicol Appl Pharmacol 1999; 154:12-19
Turnbull AV, Kim CK, Lee S, Rivier CL. Influence of carbon monoxide, and its interaction with nitric oxide, on the adrenocorticotropin hormone response of the normal rat to a physico- emotional stress. J Neuroendocrinol. 1998;10:793-802.
Turner CP, Bergeron M, Matz P, et al. Heme oxygenase-1 is induced in glia throughout brain by subarachnoid hemoglobin. J Cereb.Blood Flow Metab. 1998;18:257-73.
Verma, A., Hirsch, D.J., Glatt, C., Ronnett, G.V., and Snyder, S.H. Carbon monoxide: a putative neural messenger. Science 1993; 259(5093):381-384. [published erratum in Science 1994; 263(5143):15]
Vreman HJ, Cipkala DA, Stevenson DK. Characterization of porphyrin heme oxygenase inhibitors. Can J Physiol Pharmacol. 1996;74:278-85.
Vreman HJ, Gillman MJ, Downum KR, Stevenson DK. In vitro generation of CO from organic molecules and synthetic metalloporphyrins mediated by light. Dev.Pharmacol Ther. 1990;15:112-24.
Vreman HJ, Rodgers PA, Gale R, Stevenson DK. Carbon monoxide excretion as an index of bilirubin production in rhesus monkeys. J Med Primatol. 1989;18:449-60.
Vreman HJ, Stevenson DK. Heme oxygenase activity as measured by carbon monoxide production. Anal Biochem. 1988;168:31-8.
Vollerthun R, Hohler B, Kummer W. Heme oxygenase-2 in primary afferent neurons of the guinea-pig. Histochem.Cell Biol. 1996;105:453-8.
Weisiger RA, Rockey DC. Toxic waste or hormone? Carbon monoxide as a regulator of sinusoidal tone. Hepatology. 1996;24:1319-21.
Woo J, Iyer S, Cornejo MC, et al. Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32). Transpl.Immunol. 1998;6:84-93.
Zakhary R, Poss KD, Jaffrey SR, Ferris CD, Tonegawa S, Snyder SH. Targeted gene deletion of heme oxygenase 2 reveals neural role for carbon monoxide. Proc Natl Acad Sci U.S A. 1997;94:14848-53.

RE: CO's Role in Sensory Signaling, Sensitization, Adaptation and Long Term Potentiation

Bernabeu R, Princ F, de Stein ML, Fin C, Juknat AA, Batile A, Izquierdo I, Medina JH. Evidence for the involvement of hippocampal carbon monoxide production in the acquisition and consolidation of inhibitory avoidance learning. Neuroreport.1995;6:516-8
Broillet MC, Firestein S. Gaseous second messengers in vertebrate olfaction. J Neurobiol. 1996;30:49-57
Dengerink, H.A., Lindgren, F.L., and Axelsson, A. The Interaction of Smoking and Noise on Temporary Threshold Shifts. Acta Oto-Laryngologica, 1992;112:932-938
Donnay, A. On the Recognition of Multiple Chemical Sensitivity in Medical Literature and Government Policy. International J. Toxicol. 1999, 18(6):383-392. [first report linking CO to MCS and Edgar A. Poe]
Engen, T. The combined effect of CO and alcohol on odor sensitivity. Environ. Intl. 1986,12:207-210
Hansen D. [Occupationally induced anosmia due to chronic carbon monoxide effect]. HNO. 1970;18:140
Hawkins RD, Zhuo M, Arancio O. Nitric oxide and carbon monoxide as possible retrograde messengers in hippocampal long-term potentiation. J Neurobiol. 1994;25:652-65.
Fechter LD, Liu Y, Pearce TA. Cochlear protection from carbon monoxide exposure by free radical blockers in the guinea pig. Toxicol Appl Pharmacol. 1997;142:47-55.
Gelperin A, Kleinfeld D, Denk W, Cooke IR. Oscillations and gaseous oxides in invertebrate olfaction. J Neurobiol. 1996;30:110-22.
Ingi, I., and Ronnett, G.V. Direct demonstration of a physiological role for carbon monoxide in olfactory receptor neurons. J. Neurosci., 1995, 15:8214-8222
Ingi T, Cheng J, Ronnett GV. Carbon monoxide: an endogenous modulator of the nitric oxide-cyclic GMP signaling system. Neuron. 1996;16:835-42.
Kurahashi T, Lowe G, Gold GH. Suppression of odorant responses by odorants in olfactory receptor cells. Science. 1994;265:118-20.
Leinders-Zufall T, Shepherd GM, Zufall F. Regulation of cyclic nucleotide-gated channels and membrane excitability in olfactory receptor cells by carbon monoxide. J Neurophysiol. 1995;74:1498-508
Leinders-Zufall T, Shepherd GM, Zufall F. Modulation by cyclic GMP of the odour sensitivity of vertebrate olfactory receptor cells. Proc R Soc Lond B.Biol Sci. 1996;263:803-11.
McFarland RA. The effects of exposure to small quantities of carbon monoxide on vision. Ann NY Acad Sci 1970;174:301-12.
Meffert MK, Haley JE, Schuman EM, Schulman H, Madison DV. Inhibition of hippocampal heme oxygenase, nitric oxide synthase, and long-term potentiation by metalloporphyrins. Neuron. 1994;13:1225-33.
Menini A. Calcium signaling and regulation in olfactory neurons. Curr Opin Neurobiol. 1999;9:419-26.
Morales B, Bacigalupo J. Chemical reception in vertebrate olfaction: evidence for multiple transduction pathways. Biol Res. 1996;29:333-41
Poss KD, Thomas MJ, Ebralidze AK, O'Dell TJ, Tonegawa S. Hippocampal long-term potentiation is normal in heme oxygenase-2 mutant mice. Neuron. 1995;15:867-73.
Roche S, Horvath S, Gliner J, Wagner J, Borgia J. Sustained visual attention and carbon monoxide: elimination of adaptation effects. Hum Factors. 1981;23:175-84.
Seppanen A, Hakkinen V, Tenkku M. Effect of gradually increasing COHb saturation on visual perception and psychomotor performance of smoking and nonsmoking subjects. Ann Clin Res. 1977;9:314-9.
Stevens CF and Wang Y. Reversal of long-term potentiation by inhibitors of haem oxygenase. Nature 1993;364:147-149
Torre V, Ashmore JF, Lamb TD, Menini A. Transduction and adaptation in sensory receptor cells.
J Neurosci. 1995;15:7757-68.
von Restorff W, Hebisch S. Dark adaptation of the eye during carbon monoxide exposure in smokers and nonsmokers. Aviat.Space.Environ Med. 1988;59:928-31. [showing CO modulates photosensitivity]
Wright GR, Shephard RJ. Carbon monoxide exposure and auditory duration discrimination. Arch Environ Health. 1978;33:226-35
Zenk H. [Effects of occupationally caused carbon monoxide intoxications on the organs of smell, hearing and equilibrium]. Z. Laryngol. Rhinol.Otol. 1965;44:821-8
Zhuo M, Scott AS, Kandel RR and Hawkins RD. Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 1993;260:1946-1950.
Zufall F. and Leinders-Zufall T. Identification of a long-lasting form of odor adaptation that depends on the carbon monoxide/cGMP second-messenger system. J Neurosci. 1997;17:2703-12
Zufall F. and Leinders-Zufall T. Role of cyclic GMP in olfactory transduction and adaptation. Ann N Y Acad Sci. 1998;855:199-204

RE: Clinical Profile of Chronic Carbon Monoxide Poisoning (case series)

Beck, H.G. The clinical manifestations of chronic CO poisoning. Ann. Clinical Med, 1927; 5:1088-1096.
Beck, H.G. Slow CO asphyxiation: a neglected clinical problem. JAMA, 1936; 107:1025-1029.
Beck, H.G., Suter, G.M. Role of CO in the causation of myocardial disease. JAMA, 1938;110:1982-1986
Halpern JS. Chronic occult carbon monoxide poisoning. J Emerg Nurs 1989;15(2(Pt 1)):107-11
Luden, G. Chronic carbon monoxide poisoning. Mod. Med. 1921;3:27
Myers RA, DeFazio A, Kelly MP. Chronic carbon monoxide exposure: a clinical syndrome detected by neuropsycho-logical tests. J Clin Psychol 1998;54(5):555-67
Wilmer, W.H. Effects of carbon monoxide upon the eye. Am J Opthamology, 1921; 73-90.

RE: COHb, Pulse Oximetry and pH as Unreliable Indicators of CO Poisoning

Bazeman, W.P., Myers, R.A. and Barish, R.A. Confirmation of the pulse oximetry gap in carbon monoxide poisoning. Ann Emerg Med 1997, 30(5):608-11.
Goldbaum, L.R., Orellan,T. and Dergal, E. Joint Committee on Aviation Pathology: XVI. Studies on the relation between carboxyhemoglobin and toxicity. Aviat Space Environ Med 1977;48(10):969-70.
Groszek B, Szpak D, Nitecki J, Brodkiewicz A. The usefulness of carboxyhemoglobin, methemoglobin and blood lactate concentration in evaluating the health condition of Krakow inhabitants exposed to primary pollutants. Przegl Lek. 1996;53:338-41. (showing COHb is same in chronic CO cases v. controls)
Lebby TI, Zalenski R, Hryhorczuk DO, Leikin JB. The usefulness of the arterial blood gas in pure carbon monoxide poisoning. Vet Hum Toxicol. 1989;31:138-40.
Mahoney JJ, Vreman HJ, Stevenson DK, Van Kessel AL. Measurement of carboxyhemoglobin and total hemoglobin by five specialized spectrophotometers (CO-oximeters) in comparison with reference methods. Clin Chem. 1993;39:1693-700.
Myers, R.A. and Britten, J.S. Are arterial blood gases of value in treatment decisions for carbon monoxide poisoning? Crit Care Med 1989 Feb;17(2):139-42.
Ramirez RG, Albert SN, Agostini JC, Basu AP, Goldbaum LR, Absolon KB. Lack of toxicity of transfused carboxyhemoglobin red blood cells and carbon monoxide inhalation. Surg Forum. 1974;25:165-8.
Sanchez, R., Fosarelli, P., Felt, B., Greene, M., Lacovara, J. and Hackett, F. Carbon monoxide poisoning due to automobile exposure: disparity between carboxyhemoglobin levels and symptoms of victims. Pediatrics 1988, 82(4):663-6.
Seger D, and Welch L. Carbon monoxide controversies: neuropsychologic testing, mechanism of toxicity, and hyperbaric oxygen. Ann Emerg Med 1994;24(2):242-8
Smith SR, Steinberg S, Gaydos JC. Errors in derivations of the Coburn-Forster-Kane equation for predicting carboxyhemoglobin. Am Ind Hyg Assoc J. 1996;57:621-5.
Sokal JA. Lack of the correlation between biochemical effects on rats and blood carboxyhemoglobin concentrations in various conditions of single acute exposure to carbon monoxide. Arch Toxicol. 1975;34:331-6.
Tikuisis P, Madill HD, Gill BJ, Lewis WF, Cox KM, Kane DM. A critical analysis of the use of the CFK equation in predicting COHb formation. Am Ind Hyg Assoc J. 1987;48:208-13

RE: CO In Breath and Other Sensitive But Non-Specific Indicators of CO Exposure or Disease

Chan GC, Lau YL, Yeung CY. End tidal carbon monoxide concentration in childhood haemolytic disorders. J Paediatr.Child Health. 1998;34:447-50.
Cox BD, Whichelow MJ. Carbon monoxide levels in the breath of smokers and nonsmokers: effect of domestic heating systems. J Epidemiol Community.Health. 1985;39:75-8.
TJ, MacDonald MJ, Zerbe GO, Petty TL. Reinforcing breath carbon monoxide reductions in chronic obstructive pulmonary disease. Drug Alcohol Depend. 1991;29:47-62.
De Reuck J, Decoo D, Lemahieu I, et al. A positron emission tomography study of patients with acute carbon monoxide poisoning treated by hyperbaric oxygen. J Neurol. 1993;240:430-4.
Fix AJ, Daughton DM, Kass I, Bell CW, Wass A. Immediate carbon monoxide estimates and self-reported smoking. Percept.Mot.Skills. 1979;49:675-8.
He F, Liu X, Yang S, et al. Evaluation of brain function in acute carbon monoxide poisoning with multimodality evoked potentials. Environ Res. 1993;60:213-26.
Horvath I, Loukides S, Wodehouse T, Kharitonov SA, Cole PJ, Barnes PJ. Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress. Thorax. 1998;53:867-70.
Horvath I, Donnelly LE, Kiss A, Paredi P, Kharitonov SA, Barnes PJ. Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress. Thorax. 1998;53:668-72.
Horvath I, Barnes PJ. Exhaled monoxides in asymptomatic atopic subjects. Clin Exp Allergy. 1999;29:1276-80.
Hunter K, Mascia M, Eudaric P, Simpkins C. Evidence that carbon monoxide is a mediator of critical illness. Cell Mol.Biol (Noisy.-le.-grand.). 1994;40:507-10.
Jalukar V, Penney DG, Crowley M, Simpson N. Magnetic resonance imaging of the rat brain following acute carbon monoxide poisoning. J Appl Toxicol. 1992;12:407-14.
Kirkham AJ, Guyatt AR, Cumming G. Alveolar carbon monoxide: a comparison of methods of measurement and a study of the effect of change in body posture. Clin Sci. 1988;74:23-8. [showing supine CO greater than erect CO]
Kurt TL, Anderson RJ, Reed WG. Rapid estimation of carboxyhemoglobin by breath sampling in an emergency setting. Vet Hum Toxicol. 1990;32:227-9.
Paredi P, Biernacki W, Invernizzi G, Kharitonov SA, Barnes PJ. Exhaled carbon monoxide levels elevated in diabetes and correlated with glucose concentration in blood: a new test for monitoring the disease? Chest. 1999;116:1007-11.
Paredi P, Shah PL, Montuschi P, et al. Increased carbon monoxide in exhaled air of patients with cystic fibrosis. Thorax. 1999;54:917-20.
Pracyk JB, Stolp BW, Fife CE, Gray L, Piantadosi CA. Brain computerized tomography after hyperbaric oxygen therapy for carbon monoxide poisoning. Undersea.Hyperb.Med. 1995;22:1-7.
Risser NL, Belcher DW. Adding spirometry, [breath] carbon monoxide, and pulmonary symptom results to smoking cessation counseling: a randomized trial. J Gen Intern Med. 1990;5:16-22.
Stewart, R.D., Stewart, R.S., Stamm, W., and Seelen, R.P. Rapid estimation of carboxyhemoglobin level in fire fighters. JAMA, 235,390-392,1976.Uasuf CG, Jatakanon A, James A, Kharitonov SA, Wilson NM, Barnes PJ. Exhaled carbon monoxide in childhood asthma. J Pediatr. 1999;135:569-74.
Verhoeff AP, van der Velde HC, Boleij JS, Lebret E, Brunekreef B. Detecting indoor carbon monoxide (CO) exposure by measuring CO in exhaled breath. Int Arch Occup Environ Health 1983;53(2):167-73
Vreman HJ, Baxter LM, Stone RT, Stevenson DK. Evaluation of a fully automated end-tidal carbon monoxide instrument for breath analysis. Clin Chem. 1996;42:50-6.
Wickramatillake HD. Validation of the end-expired method for measuring carboxyhaemoglobin levels for the use in occupational and environmental exposure studies. Occup Med (Lond). 1999;49:43-5.
Yamaya M, Sekizawa K, Ishizuka S, Monma M, Mizuta K, Sasaki H. Increased carbon monoxide in exhaled air of subjects with upper respiratory tract infections. Am J Respir Crit Care Med.1998;158:311-4
Zayasu K, Sekizawa K, Okinaga S, Yamaya M, Ohrui T, Sasaki H. Increased carbon monoxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med. 1997;156:1140-3.

RE: Effect of 100% Oxygen (O2) on Blood O2 Content, O2 Pressure (PO2) and O2 Delivery

Fox, S.I., Human Physiology [5th Edition] Dubuque, IA: William C. Brown Publishers, 1996, page 478:

"An increase in blood P[a]O2 -- produced, for example, by breathing 100% oxygen from a gas tank -- thus cannot significantly increase the amount of oxygen contained in the red blood cells. It can, however, significantly increase the amount of oxygen dissolved in the [arterial] plasma because the amount dissolved is directly determined by the PO2. If the PO2 doubles, the amount of oxygen dissolved in the plasma also doubles, but the total oxygen content of whole blood increases only slightly, since most of the oxygen by far is not in plasma but in the red blood cells [tightly bound to hemoglobin]. Since the oxygen carried by red blood cells must first dissolve in plasma before it can diffuse to the tissue cells, however, a doubling of [arterial] blood PO2 [or a halving of the venous PO2] means that the rate of oxygen diffusion to the tissues would double under these conditions. For this reason, breathing from a tank of 100% oxygen would signifi-cantly increase oxygen delivery to the tissues, although it would have little effect on the total oxygen content of blood." [comments and emphasis added]

RE: Treatment of Carbon Monoxide Poisoning with Normobaric 100% Oxygen

Hardy, K.R. and Thom, S.R. Pathophysiology and treatment of carbon monoxide poisoning. J Toxicol Clin Toxicol 1994;32(6):613-29.
Kirkham, A.J., Guyatt, A.R. and Cumming, G. Alveolar carbon monoxide: a comparison of methods of measurement and a study of the effect of change in body posture [showing that the level of expired CO increases as the concentration of inhaled oxygen increases]. Clin Sci 1988, 74:23-28.
Meert, K.L., Heidemann, S.M., and Sarnaik, A.P. Outcome of children with carbon monoxide poisoning treated with normobaric oxygen. J Trauma 1998, 44(1):149-54.
Scheinkestel, C.D., Bailey, M., Myles, P.S., Jones, K., Cooper, D.J., Millar, I.L., et al. Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomized controlled clinical trial. Med J Australia 1999; 170: 203-210.
Tibbles, P.M., Perrotta, P.L. Treatment of carbon monoxide poisoning: a critical review of human out-come studies comparing normobaric oxygen with hyperbaric oxygen. Ann Emerg Med 1994; 24:269-276.
Weaver, L.K. Carbon monoxide poisoning. Crit Care Clin 1999, 15(2):297-317.

INFORMATION ON-LINE

http://www.mcsrr.org (homepage of MCS Referral & Resources with link to the Poe- Awareness poster)

http://www.carbonmonoxide.org (links to CO webpages and discussion lists)

http://www.phymac.med.wayne.edu/FacultyProfile/penney/COHQ/co1.htm (Dr. Penney's CO Headquarters)

6. RESOURCES

Oxygen Tanks or Concentrators (capable of generating 90% oxygen at 6 liters per minute)

For home delivery of compressed or liquid oxygen or to rent an oxygen concentrator–each available only by prescription--check in your local yellow pages under "oxygen" for accredited suppliers. Most accept Medicare and private insurance as full payment, but if paid out of pocket, the total cost for oxygen, tubing, setup, and service should be less than the $225 per month that Medicare pays for continuous supplemental oxygen, regardless of modality (liquid is most common). Oxygen concentrators that reach 90% O2 at 6 liters per minute–sufficient for this protocol--can be bought new for $1000 to $2000 or used from MCS R&R for $500 (refurbished by factory certified technicians with a full 3-year warranty, call 410-889-6666 for details). Regardless of which option is selected, be sure a respiratory therapist comes to the patient's home to set up and demonstrate the equipment. This should include a regulator valve that can adjust the flow to at least 6 liters per minute connected via flexible tubing to a cannulus (or to a non-rebreather plastic or ceramic mask if prefered). The flow rate, percent oxygen, and all these components should be specified in the physician's prescription.

Oxygen Tubing and Non-Rebreather Masks

Some patients cannot tolerate using standard oxygen tubing and masks because of the chemicals these give off when new. In such cases, patients should try using stainless steel tubing and a ceramic canulus or mask. These, and cellophane non-rebreather bags, are available from the American Environmental Health Fdn (800-428-2343). For those who also cannot tolerate ceramic masks, Dr. Trep Piamonte of the Dallas Environmental Health Center makes a small aluminum one ($35, available from him directly, 214-373-5126.

Low-Level Carbon Monoxide Monitors for People at Greater Risk of CO Poisoning

MCS Referral & Resources used to distribute the IST-AIM 935 digital CO Monitor designed by Albert Donnay, the only CO detector that displays from 5ppm and provides instantaneous warnings above the US EPA limits of 9 and 35ppm. Unfortunately it is no longer in production, but two other portable CO detectors that can display below 30ppm (one from 0 and the other from 10ppm) are available for approx. $130 each from www.aeromedix.com . In comparison, regular CO Alarms do not display CO levels under 30ppm and do not go off until over 70ppm for one to four hours.

Carbon Monoxide Breath Analyzers (displays from 0 - 999ppm, gives warning above 35ppm)

Since breathing 100% oxygen increases the concentration of exhaled CO, physicians may want to monitor both exhaled O2 and CO levels before and after treatment. MCS R&R director Albert Donnay has worked with Biosystems to customize an air monitorning instrument for breath analysis. The MultiPro, which is the size of a fat cell phone, not only measures both O2 and CO, it also detects hydrogen sulfide down to 0.1ppm. H2S, like CO, is made endogenously and acts as a sensory neurotransmitter.

Edgar Allan Poe Carbon Monoxide Awareness Poster

MCS R&R offers an 11x17 inch poster entitled "The Tell-Tale Signs of Carbon Monoxide Poisoning" featuring the face of Edgar Allan Poe and information about symptoms, sources, effects, populations at risk and treatment. Designed for display in physician offices and emergency rooms. Single copies are free, rolled copies mailed in protective tubes are $1 each (minimum 5).

7. ACKNOWLEDGEMENTS

This protocol could not have been written without the invaluable input of many physicians, respiratory therapists and their patients. Special thanks are due to Dr. William Rea and Dr. Amado Piamonte at the Dallas Environmental Health Center, Dr. Ann McCampbell, and Dr. Larry Plumlee -- although final responsibility for the protocol rests with MCS Referral & Resources, to whom any comments should be addressed: 410-889-6666, fax 410-889-4944, email adonnay@mcsrr.org

RETURN TO LIST OF ARTICLES

Last Modified: 10/26/2006

Background on Sources, Symptoms, Biomarkers and Treatment of Chronic Carbon Monoxide Poisoning

by Albert Donnay, MHS, Environmental Health Engineering President, MCS Referral & Resource

Contents