Argyria (ISV from Greek: αργύρος argyros silver + -ia) is a disease caused by the ingestion of elemental silver, silver dust or silver compounds. The most dramatic effect of argyria is that the skin is colored blue or bluish-grey. Argyria may be found as generalized argyria or local argyria. Argyrosis is the corresponding condition related to the eye. The condition is believed to be permanent. Most recent cases are due to the over consumption of home made colloidal silver as an alternative medicine.

Since at least the early part of the 20th century, doctors have known that silver or silver compounds can cause some areas of the skin and other body tissues to turn gray or blue-gray. Argyria occurs in people who eat or breathe in silver over a long period (several months to many years). A single exposure to a silver compound may also cause silver to be deposited in the skin and in other parts of the body; however, this is not known to be harmful. It is likely that many exposures to silver are necessary to develop argyria. Once argyria develops, it is believed to be permanent. However, the condition is thought to be only a "cosmetic problem". Most doctors and scientists believe that the discoloration of the skin seen in argyria is the most serious health effect of silver (in small doses).

Reports of cases of argyria suggest that gram amounts (from 2 to 4 grams) of silver or a silver compound taken in medication in small doses over several months may cause argyria in some humans. People who work in factories that manufacture silver can also breathe in silver or its compounds. In the past, some of these workers have become argyric. However, the level of silver in the air and the length of exposure that caused argyria in these workers is not known. It is also not known what level of silver causes breathing problems, lung and throat irritation, or stomach pain in people. Studies in rats show that drinking water containing very large amounts of silver (9.8 grams of silver per U.S. gallon water or 2.6 grams per liter) is likely to be life-threatening.

There is very little information about health effects following skin contact with silver compounds. Argyria that covers the entire body is not seen following skin contact with silver compounds, although the skin may change color where it touches the silver. However, many people who have used skin creams containing silver compounds such as silver nitrate and silver sulfadiazine have not reported health problems from the silver in the medicine. In one animal study, a strong solution of silver nitrate (81 milligrams silver nitrate per liter of water) applied to the skin of guinea pigs for 28 days did not cause the animals to die; however, it did cause the guinea pigs to stop gaining weight normally. It is not known if this would happen to people if they were exposed the same way.

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Nosocomial Urinary Tract Infections And the Indwelling Catheter: What Is New and What Is True?
From CHEST, 7/1/01 by Calvin M. Kunin

What Is New and What Is True?

The urinary catheter is an essential part of modern medical care. It is widely used to relieve anatomic or physiologic obstructions, to provide a dry environment for comatose or incontinent patients, and to permit the accurate measurement of urinary output in severely ill patients. Unfortunately, when used inappropriately or when left in place too long, it is a hazard to the very patients that it is designed to protect. Catheter-associated urinary infections account for about 40% of all nosocomial infections and increase the duration of hospital stays, the costs, and mortality.[1,2] Systemic antimicrobial therapy may temporarily reduce the bacterial count in the bladder urine but cannot eradicate infections in patients with indwelling urinary catheters.[3,4] Inappropriate and excessive use of antimicrobial drugs leads to the selection of antibiotic-resistant microorganisms and nosocomial outbreaks of infection with multiresistant strains.

One would expect that prevention of catheter-associated infection would have a very high priority for research sponsored by the government and the health-care industry. The Centers for Disease Control and Prevention (CDC) and hospitals continue to emphasize surveillance. This helps to document the problem, but does not provide solutions. The CDC guidelines for the prevention of catheter-associated infections have not been updated since 1983.[5] The National Institutes of Health sponsor a great deal of research focused on the molecular mechanisms of sepsis but not on the cause. Most of the innovations in this field have come from the equipment manufacturers. There has been very little motivation for true innovation except for the relatively recent development of antimicrobial impregnated catheters. Catheters and drainage bag systems are considered to be a commodity competing for the lowest expenditures that hospitals will support. There appears to be minimal oversight by the Food and Drug Administration. The only effective control is competition among manufacturers and the efforts of a small cadre of devoted clinical investigators.

The mechanisms by which the indwelling catheters produce infection are now well established. These consist initially of ascending colonization of the urine within the catheter lumen and eventually along the space between the urethra and the catheter surface. The technologic requirements to design better catheters and drainage systems are fairly well-known.[6] Dukes[7] demonstrated the efficacy of closed drainage to block ascending infection in 1928. Disposable closed drainage systems became widely available almost 40 years ago.[8] None of the numerous attempts to improve the system have been shown to be more effective than simple closed drainage. In the this issue of CHEST, Leone and colleagues (see page 220) found no difference in the acquisition of bacteriuria between a simple two-chamber drainage bag and a complex system consisting of a preconnected coated latex catheter, a tamper-discouraging seal, a drip-chamber, an antireflux valve, a drainage bag vent, and a povidone-iodine-releasing cartridge at the drain port. It is surprising that this complex system is still on the market since all of these measures have been shown to be ineffective.[9-11] The only truly novel drainage bag that I am aware of is a nonreusable system containing a water-absorbing polymer that traps bacteria and urine.[12] It is purported to avoid ascending infection and cross-contamination, but this needs to be evaluated in properly conducted controlled trials.

Attempts to block the periurethral route by coating catheters with antimicrobial agents are currently receiving considerable attention. These agents include silver oxide,[13,14] silver hydrogel (silver alloy),[15-18] nitrofurazone,[19,20] and combinations of minocycline and rifampin.[21,22] The current favorites are the catheters coated with silver alloy and nitrofurazone. Nitrofurazone has been shown[19] to be superior to silver hydrogel according to in vitro studies of activity against microorganisms that commonly cause catheter-associated infection. Some of the clinical trials are well-designed prospective studies that determine the daily rate of acquisition of bacteriuria. Others are crossover studies that use clinical criteria to identify patients with infections. The crossover studies are usually not blinded and do not provide daily end points. It is, therefore, somewhat difficult to assess their true efficacy in preventing acquisition of bacteriuria. For example, a preliminary account of a double-blind, prospective study[15] of a silver-hydrogel-coated catheter reported a decrease in infections caused by enterococci, coagulase-negative staphylococci, and Candida but showed little effect against Gram-negative bacilli. The same authors[20] reported a fivefold reduction of the acquisition of bacteriuria with a nitrofurazone-impregnated catheter, but the reduction did not reach statistical significance. On the other hand, trials using clinical end points report reductions in the incidence of symptomatic urinary tract infections of 47%[16] and 21%.[18] A clinical trial[22] of the catheters coated with minocycline and rifampin found a significantly reduced rate of Gram-positive, but not Gram-negative, bacteriuria.

Several points need to be considered before hospitals decide to purchase impregnated catheters. These include an approximately sixfold greater cost and lack of efficacy once bacteriuria is acquired. It does not seem appropriate to use these more expensive catheters in medical or surgical patients who require only a few days of drainage or in long-term care facilities where virtually all of the patients are already infected. The allocation of catheters can become a logistical nightmare for hospitals. Often it is difficult to predict how long a catheter will be needed, particularly in ICUs. The determination of the acquisition of bacteriuria requires periodic cultures and increases costs. Although silver and nitrofurazone catheters have been reported to be safe in clinical trials, it is possible that allergies or other adverse effects may occur with more widespread use. We need to remind ourselves that until recently latex was considered to be safe. All latex products had to be removed from hospitals because of a few, but important, allergic reactions. Argyria is a potential problem for long-term-care patients. Furthermore, silver-resistant mutants of Escherichia coli can be selected by stepwise exposure.[23]

Catheters are fairly rigid structures. They drain the bladder, but they block the urethra. The challenge is to produce an instrument that matches as closely as possible the normal physiologic and mechanical characteristics of the voiding system. This requires construction of a thin-walled, continuously lubricated, collapsible (conformable) catheter to protect the integrity of the urethra[24]; a system to hold the catheter in place without a balloon; and measures to imitate the intermittent washing of the bladder urine. The efficacy of each component of the system will need to be evaluated in carefully conducted, controlled clinical trials. There is also a major need for better fitting male condom catheters and for external urine collection devices for incontinent women. Catheters of the future may be more expensive but may be well worth the investment if used in the appropriate population.

There is no need to wait for a mechanical or chemical answer to the problem of nosocomial urinary tract infections. The culprits are unnecessary and prolonged use of catheters when they are no longer needed.[25] Oliguric patients do not need catheters. Urine output can be measured using noninvasive portable ultrasound devices. Bladder ultrasound combined with intermittent catheterization, as needed, or condom drainage should help to eliminate catheter use in ICUs except during massive hydration. It may be possible to develop a recording bladder ultrasound device that can measure urine output in real time. This might replace the urinary catheter to measure urine output in ICUs just as ear oximeters have replaced intra-arterial lines for the measurement of BP and blood gases.

Improvements in catheter and drainage bags are needed, but these cannot substitute for thoughtful care. We must ask ourselves on daily rounds: "Is this catheter really needed? When can I take it out? Are there alternate measures? Can a portable ultrasound help determine when a catheter may be needed?"

REFERENCES

[1] Kunin CM. Urinary tract infections detection. In: Kunin CM, ed. Urinary tract infections: detection, prevention and management. 5th ed. Baltimore, MD: Williams & Wilkins, 1977

[2] Centers for Disease Control and Prevention. Public health focus: surveillance, prevention and control of nosocomial infections. MMWR Morb Mortal Wkly Rep 1992; 41:783-787

[3] Britt MR, Garibaldi RA, Miller WA, et al. Antimicrobial prophylaxis for catheter-associated bacteriuria. Antimicrob Agents Chemother 1977; 11:240-243

[4] Warren JW, Anthony WX, Hoopes JM, et al. Cephalexin for susceptible bacteriuria in afebrile, long term catheterized patients. JAMA 1982; 248:454-458

[5] Wong ES. Guidelines for prevention of catheter-associated urinary tract infections. Am J Infect Control 1983; 11:28-33

[6] Kunin CM. Can we build a better urinary catheter? N Engl J Med 1988; 319:365-366

[7] Dukes C. Urinary infections after excision of the rectum: their cause and prevention. Proc R Soc Med 1928; 22:1-11

[8] Kunin CM, McCormack RC. Prevention of catheter-induced urinary-tract infections by sterile closed drainage. N Engl J Med 1966; 274:1155-1161

[9] Thompson RL, Haley CE, Searcy MA, et al. Catheter-associated bacteriuria: failure to reduce attack rates using periodic instillations of a disinfectant into urinary drainage systems. JAMA 1984; 251:747-751

[10] Huth TS, Burke JP, Larsen RA, et al. Clinical trial of junction seals for the prevention of urinary catheter-associated bacteriuria. Arch Intern Med 1992; 152:807-812

[11] Monson TP, Macalalad FV, Hamman JW, et al. Evaluation of a vented drainage system in prevention of bacteriuria. J Urol 1977; 117:216-219

[12] PathoSorb Drainage system [package insert]. Emeryville, CA: Eastman Medical Products, 1997

[13] Johnson JR, Roberts PL, Olsen RJ, et al. Prevention of catheter-associated urinary tract infection with a silver oxide-coated urinary catheter: clinical and microbiologic correlates. J Infect Dis 1990; 162:1145-1150

[14] Riley DK, Classen DC, Stevens LE, et al. A large randomized clinical trial of a silver-impregnated urinary catheter: lack of efficacy and staphylococcal superinfection. Am J Med 1995; 98:349-356

[15] Maki DG, Knasinski V, Halvorson K, et al. A novel silver-hydrogel-urinary catheter reduces catheter associated urinary tract infections: a prospective, randomized, double blind trial [abstract]. In: Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1998; 523 (abstract K-113)

[16] Saint S, Elmore JG, Sullivan SD, et al. The efficacy of silver-coated urinary catheters in preventing urinary tract infections: a meta-analysis. Am J Med 1998; 105:236-241

[17] Saint S, Veenstra DL, Sullivan SD, et al. The potential clinical and economic benefits of silver alloy urinary catheters in preventing urinary tract infection. Arch Intern Med 2000; 160:2670-2675

[18] Karchmer TB, Giannetta ET, Muto CA, et al. A randomized crossover study of silver-coated urinary catheters in hospitalized patients. Arch Intern Med 2000; 160:3294-3298

[19] Johnson JR, Delavari P, Azar M. Activities of a nitrofurazone-containing urinary catheter and a silver hydrogel catheter against multidrug-resistant bacteria characteristic of catheter-associated urinary tract infection. Antimicrob Agents Chemother 1999; 43:2990-2995

[20] Maki DG, Knasinski V, Tambyah PA. A prospective investigator-blinded trial of a novel nitrofurazone-impregnated indwelling urinary catheter [abstract]. Infect Control Hosp Epidemiol 1997; 18(suppl):50 (abstract M49)

[21] Darouiche RO, Safar H, Raad II. In vitro efficacy of antimicrobial-coated bladder catheters in inhibiting bacterial migration along catheter surfaces. J Infect Dis 1997; 176:1109-1112

[22] Darouiche RO, Smith JA Jr, Hanna H, et al. Efficacy of antimicrobial-impregnated bladder catheters in reducing catheter-associated bacteriuria: a prospective, randomized, multicenter clinical trial. Urology 1999; 54:976-981

[23] Li X-Z, Nikaido H, Williams KE. Silver-resistant mutants of Escherichia coli display efflux of Ag+ and are deficient in porins. J Bacteriol 1997; 179:6127-6132

[24] Brocklehurst C, Hickey DS, Davies I, et al. A new urethral catheter. BMJ 1988; 296:1691-1693

[25] Jain P, Parada JP, David A, et al. Overuse of the indwelling urinary catheter in hospitalized medical patients. Arch Intern Med 1995; 155:1425-1429

Dr. Kunin is Emeritus Professor, Department of Internal Medicine, The Ohio State University.

Correspondence to: Calvin M. Kunin, MD, Department of Internal Medicine, The Ohio State University, M110 Starling Loving Hall, 320 West 10th Avenue, Columbus, Ohio 43210; e-mail: ckunin@columbus.rr.com

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