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Operating Room & Infection Control

Pesky Pyrogens, Endotoxins

Restrictions needed on more medical devices and gloves to prevent contamination

by Milt Hinsch

yrogens and endotoxins have no flashing lights, honking horns or crashing cymbals. They are sneaky, pesky components of dead bacteria that can wreak havoc in the body. Should infection preventionists, medical personnel, surgeons, surgical nursing teams and OR managers be concerned about pyrogens and endotoxins? After all, aren't all medical devices used inside the body regulated by the FDA to be "non-pyrogenic"? "Yes," we need to be concerned about pyrogens and endotoxins, and "no," the FDA fails to require that all medical devices used inside of the body be non-pyrogenic. However, when reviewing the literature there is a lot more to this than a simple "yes" and "no."

P

Pyrogens Have Nothing to Do with Fireworks!

Some people confuse the term "pyrogenic" with fireworks, which is a natural mistake. Fireworks are called "pyrotechnics" while a pyrogen

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is "a fever-producing substance,"1 it does not produce fireworks--thank goodness! Fireworks shooting from body orifices would be disconcerting, no doubt. Both "pyrotechnics" and "pyrogenic" start with the root word "pyro," which is a Greek word that means "fire." Pyrogens can come from a chemical found in the outer envelope of dead bacteria. Although some chemicals, a few drugs and some chemotherapy agents are pyrogenic,2 the focus here is on pesky pyrogens from bacteria.

Endotoxins Come from the OUTER Membrane of the OUTER Cell Wall-- So, Why Are They Called ENDOtoxins?

Endotoxins, come from the outer membrane of the cell wall of dead, gram-negative bacteria and consist of toxic lipopolysaccharides (LPS)3 They are contained within the body of a bacterium (thus called ENDOtoxin) and freed only when the bacterium is broken down.4

Although the bacteria are dead, some of their cell wall components can react within the human body to cause a fever. That is what makes them so pesky. Pyrogens and endotoxins still produce biochemical reactions even though the bacteria that produced them are dead. Endotoxins cause pyrogenic reactions. So, speaking generally about pyrogens and endotoxins, all endotoxins are pyrogens, but not all pyrogens are endotoxins. "Microbial pyrogens," as opposed to "gram-negative bacterial endotoxins," has become a general descriptive term for many different substances. However, pyrogenic substances can be produced by some gram-positive bacteria, mycobacteria, fungi and also viruses, but the pyrogens produced by gram-negative bacteria, i.e., the endotoxins, are of significance to the medical device and pharmaceutical industries.5 Bacterial endotoxins, found in the outer membrane of gram-negative bacteria are members of a class of phospholipids called lipopolysaccharide (LPS). LPS is not the same as the exogenous toxins produced by gram-negative or gram-positive bacteria. Release of LPS from bacteria takes place after death and lysis of the cell. Good examples of pyrogen-producing, gram-negative bacteria are Escherichia coli, Proteus, Pseudomonas, Enterobacter and Klebsiella.6 Endotoxin is toxic to the body and can cause multiple, severe reactions, organ failure and even death. Reactions include lymphocyte migration, histamine release, vasodilation, inflammation, coagulation, thrombosis, and acute disseminated intravascular coagulation, which depletes platelets and various clotting factors and result in internal bleeding. Plasmin activation by endotoxins leads to fibrinolysis and hemorrhaging. Kinin activation releases bradykinins and other vasoactive peptides, which causes hypotension. The net effect is that endotoxins can induce inflammation, intravascular coagulation, hemorrhage, shock and death.7 Endotoxin-induced multiple-organ failure continues to be a major health problem, particularly in intensive care; it has been estimated that as many as 50,000 deaths occur annually in the United States as the result of endotoxininduced shock.8 On the other hand, some deaths that might appear to be from endotoxins are actually the results of bacterial exotoxins--toxins excreted by bacterial pathogens. Perhaps some remember the documented deaths from tampon-related "toxic shock syndrome (TSS)" from many years ago? TSS was the result of high levels of toxin-producing, gram-positive, Staphlyococcus aureus strain that was believed to have released one or more toxins into the bloodstream. TSS clearly demonstrates the difference between bacterial exotoxins and endotoxins. Endotoxins come from dead gram-negative bacteria while the TSS toxins come from living gram-positive bacteria (S. aureus).9

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The discovery that pyrogens contaminated surgical gloves, could contaminate devices being inserted into patients, and could increase patients' febrile responses, alerted the surgical glove manufacturers to potential problems resulting from pyrogen and endotoxin contamination.

How Many Bacteria Does it Take to Screw in an Endotoxin Light Bulb?

Minuscule amounts of endotoxins can harm human tissues. It takes only 263 dead gram-negative bacteria to elicit clinical reactions. And just 263 dead E. coli can contain enough endotoxin to exceed the allowable Food and Drug Administration (FDA)/United States Pharmacopeia (USP) limit for endotoxins on cerebrospinal fluid (CSF) contact devices.10 For non-CSF-contact devices, the FDA/USP limit is 20 Endotoxin Units (EUs) per device. One Endotoxin Unit contains only 100 picograms (1pg= 1x10-12g) of E. coli polysaccharide--the amount of polysaccharide present in around 105 bacteria.11,12 Medical fluids such as sterile water for injection have an allowable endotoxin limit of 0.25 Endotoxin Units per milliliter. Bacteriostatic water for injection and sterile water for inhalation are limited to 0.5 Endotoxin Units per milliliter. In humans, the minimum clinical dose of endotoxins is only 5 EUs/Kg of body weight.13 Therefore, if you weigh 220 pounds, only 50,000 picograms, or 50 x10-9grams, or fifty billionths of a gram are necessary to produce a clinical reaction. While endotoxins are very potent, the exotoxins produced by pathogenic bacteria are even more toxic.14

antigenic, cannot be converted to toxoids, which are toxins that are no longer toxic, but can induce formation of antibodies upon injection.16

Pyrogens on Medical Implants and Invasive Devices are Regulated--Almost

FDA requires that medical implants, items contacting the intravenous line and pharmaceuticals be "non-pyrogenic." These regulations help to protect patients from post-treatment, pyrogenic reactions.17,18 Unfortunately, the FDA has never applied the same restrictions to all surgical devices and has not required that surgical gloves or lap sponges be "non-pyrogenic."19 As early as 1982, pyrogens were reported on surgical gloves which had also contaminated angiographic catheters used in a catheterization laboratory. Simply by washing the surgical gloves with pyrogen-free water, the incidence of febrile reactions in the catheterization laboratory fell from 11.6 percent to 0.6 percent.20 The discovery that pyrogens contaminated surgical gloves, could contaminate devices being inserted into patients, and could increase patients' febrile responses, alerted the surgical glove manufacturers to potential problems resulting from pyrogen and endotoxin contamination. In addition, historical cases of medical device contamination with endotoxins following washing with endotoxin-containing water have been reported. Heart catheters were reprocessed by the hospital and were found to have been contaminated by tap water and bacterial growth in residual moisture.21 In Colorado in 1995, Endotoxin contamination in a cardiac cath lab caused the death of two patients and sickened five others. Endotoxin levels were 10 to 30 times greater than normal in the sickened patients. The source of the endotoxins was never determined.22 In 1997, "Endotoxin and Particulate Matter on Surgical Gloves" pointed to glove powder as having deleterious effects on wound healing and being a vector for latex allergens, bacteria and endotoxins. Glove powder can be contaminated with, and seems to absorb endotoxin. The researchers called upon regulatory authorities more than 10 years ago to set standards that would force glove manufacturers to improve quality during manufacture.23 Also in 1997, other researchers published an article that pointed to endotoxins as a possible adjuvant to latex allergy via tissue irritation. In addition, they hypothesized that endotoxins might be responsible for the enhancement of delayed and immediate hypersensitivity reactions to chemicals and proteins found in gloves, and offer a possible explanation for the disproportionate severity of these reactions.24 In 2008, the American Academy of Allergy Asthma and Immunology selected an article entitled "Endotoxin and

Sterilization is Ineffective Against Endotoxins? You MUST be Kidding!

Where do pyrogens and endotoxins originate on sterile medical devices? If medical instruments are sterilized, shouldn't sterilization eliminate pyrogen or endotoxin contamination? Typical sterilization temperature and humidity kills bacteria and spores, but does not remove bacterial remnants such as endotoxin polysaccharides from sterilized objects.15 Endotoxins are heat stable (boiling for 30 minutes does not destabilize endotoxin), but certain powerful oxidizing agents such as superoxide, peroxide and hypochlorite have been reported to neutralize them. Endotoxins, although

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Asthma Inflammation" from recent literature as one of the important allergy, asthma and immunology articles for that year. The article was based on a study in which researchers evaluated 17 subjects with mild allergic asthma by segmental bronchial challenge with allergen, with endotoxin and with a combination of the two. The allergen and endotoxin combination caused an increase in the numbers of total cells--lymphocytesm, neutrophils, eosinophils, monocytes and myeloid dendritic cells--in bronchoalveolar lavage fluid obtained 24 hours after challenge. In addition, they also found increased levels of IL-1 and IL-6 as well as TNF--alpha. In simple terms, that means that the combination of allergen and endotoxin increased the subjects' reactions more than allergens or endotoxins alone.25

References

1. 2. 3. 4. .5 6. 7. 8. 9. 10. 11. Taber's Cyclopedic Medical Dictionary, F.A. Davis Company, Philidelphia, PA USA. 1993 17th Edition. Emedicinehealth.com/fever_in_adults/article-em.htm Accessed April 27. 2009. Department of Health, Education and Welfare Public Health Service, Food and Drug Administration, ITG Subject: Bacterial Endotoxins/ Pyrogens Number 40 March 20, 1985. Taber's Cyclopedic Medical Dictionary, F.A. Davis Company, Philidelphia, PA USA 1993 17th Edition. Department of Health, Education and Welfare Public Health Service, Food and Drug Administration, ITG Subject: Bacterial Endotoxins/ Pyrogens Number 40, March 20, 1985. Ibid. Todar, K. Bacterial Endotoxin. Todar's Online Textbook of Bacteriology. Madison, WI 2008. McGraw-Hill Concise Encyclopedia of Bioscience 2002. Tampon Safety; FDA Consumer Magazine. United States Food and Drug Administration. March-April 2000. Wikipedia Encyclopedia, Depyrogenation, Accessed April 30, 2009. United States Pharmacopoeial Convention, Inc., Rockville, MD. Monograph Section 85 Bacterial Endotoxins, Monograph Section 151 Pyrogen Test. Transfusion and Infusion Assemblies and Similar Medical Devices Section 161. United States Pharmacopoeia 27 & National Formulary 22nd edition, Nov. 21, 2003. Ibid. Wikipedia Encycolopedia, Depyrogenation,Accessed April 30, 2009. Todar, K. Bacterial Endotoxin. Todar's Online Textbook of Bacteriology. Madison, WI. 2008. Ibid. Ibid. U.S. Food & Drug Administration, U.S. Department of Health & Human Services, U.S. Public Health Service, Guideline on Validation of the Limulus Amebocyte Lysate Test as an End Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices. December, 1987. Interim Guidance for Human and Veterinary Drug Products and Biologicals. U.S. Dept of Health & Human Service, FDA. July 1991. Ibid. Kure, R, Grendahl, H Paulssen, J. Pyrogens from Surgeons' Sterile Latex Gloves. Acta path. Microbial.immunol. scand. 1982;90B 85-88. Kundsin, R Walter, C Detection of Endotoxin on Sterile Catheters Used for Cardiac Catheterization. Journal of Clinical Microbiology. March 1980:11:209-212. Cardiac Lab Closed After Patients Stricken by Endotoxins. Biomedical Safety and Standards. Jan. 1, 1985;26;1,3. Holmdahl, L, Chegini, N. Endotoxin and Particulate Matter on Surgical Gloves. Journal of Long Term Effects of Medical Implants, 1997;3&4:225-234. Williams, Brock, Halsey, F. Endotoxin as a factor in adverse reactions to latex gloves. Annals of Allergy Asthma and Immunology, 1997;79:303-310. Schaumann F, et al. Endotoxin augments myeloid dendritic cell influx into the airways in patients with allergic asthma. American Journal of Respiratory and Critical Care Medicine 2008;177:1307-1313.

Pesky Pyrogens/Endotoxins and Powder Particles

During the last century, many articles have been written about the harmful effects of pyrogens, endotoxins and medical devices. Few of these articles focused on the contribution of endotoxins to the harmful effects of surgical gloves. Based upon the evidence, it is time for regulators to review and update regulations regarding medical glove powder and pyrogens/endotoxins--in the same way that they have already regulated medical implants, IV devices and pharmaceuticals for the protection of patients and healthcare workers. These pesky pyrogens and endotoxins are allowed to remain on medical devices unless regulators send the message that any device entering the human body must be nonpyogenic and as safe as reasonably possible. Pyrogens and endotoxins should be reduced on the few invasive medical devices that are not yet "non-pyrogenic" regulated. They should perhaps also be considered in the investigation of "GOK" (God Only Knows) cases of patients with spiked fevers and toxic shock symptoms without signs of infection.

12. 13. 14. 15. 16. 17.

18. 19. 20. 21. 22. 23. 24.

Humble Conclusion

Strong evidence ties pesky pyrogens and endotoxins to the harmful effects caused by at least one medical device not covered by pyrogen and endotoxin regulation. Pyrogens and endotoxins, which are microscopic, not easily detected and are not eliminated by typical sterilization methods can cause a myriad of patient and healthcare worker problems. Although researchers have repeatedly called for regulations to control pyrogens and endotoxins on unregulated, invasive, medical devices, those regulations have never been mandated. As more evidence emerges, the stronger the argument becomes to eliminate pesky pyrogens and endotoxins on medical gloves and on other invasive devices.

25.

Milt Hinsch is technical services director, Molnlycke Health Care, in Norcross, Ga. and has worked in the medical glove industry for more than 25 years.

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