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The Controlled Use of Copper as an Antibacterial Agent in Respiratory Therapy Apparatus
COMMUNICATIONS TO THE EDITOR
202
to be a trend in these large groups, particularly in view of the more serious illness in our MINCA group as compared to the control group. The two groups were very similar as to sex distribution and average age. The number of patients with pneumonia, diabetes mellitus, and cancer treated in the MINCA unit during the five-month evaluation period was too small for adequate mortality comparisons. There was no statistical difference in the total hospital stay in the MINCA group compared to the control group. Health care activity rate is a measurement of total professional and nursing care per day, and was significantly greater for MINCA patients in eight of nine disease categories, compared to the controls. Edward I. Elisberg, M.D.o Highland Park, Illinois "Chairman, Department of Medicine, Highland Park Hospital; Assistant Professor of Medicine, Northwestern University Medical School, Chicago. REFERENCES
1 Jeffers WN: Acute beds only? Med Econ 45: 191, 1968 2 Listi SA: Constant care unit. Hospitals 44:41, 1970 3 Grace WJ, Yarvote PM: The intermediate coronary care unit-preliminary observations. Clin Res 17:579, 1969
The Controlled Use of Copper as an Antibacterial Agent in Respiratory Therapy Apparatus To the Editor:
A successful reduction in the incidence of pulmo. nary infection in patients on IPPB therapy by the continuing sterilization by copper of the nebulizer reservoir and effluent air has been achieved by Dr. Deane and co-workers 1 (Chest 58:373, October, .1970). However, the use of a 10 to 20 gram copper scouring pad in the reservoir introduces an unwarranted risk of copper poisoning to these patients, particularly to those on longterm. therapy. Although the reported level of copper in the nebulizer of 194 JA-g/100 ml would expose the patient to less than 4 mg of copper per day, any acidity in the water could very readily increase the dissolved copper to danger levels." Such acidity could derive from the local water source, from incomplete removal of the acetic acid used to clean the copper scouring pad or to sterilize the equipment, or from accumulation of carbon dioxide from ambient air. The latter possibility is suggested in
the observed increase in reservoir copper from 9.5 p.g/100 ml at four hours to 194 p.g/l00 ml at eight hours. Copper dissolved from a copper heat exchanger by acid water from an exhausted de ionizer has caused acute hemolytic and gastrointestinal episodes, at times fatal, in a number of patients undergoing hemodialysis. 3. 4 The moderately raised plasma total copper levels shown in the majority of Dr. Deane's patients on longterm IPPB therapy could be due to a harmless increase in the copper-containing protein, ceruloplasmin, because of infection or oral contraceptives, but could also be due to an increase of the free, potentially toxic, ionic copper of the plasma, which is transported by the albumen, and which normally ranges from 5 to 15 p.g/l00 mI. 5 Excessive amounts of this free copper are rapidly removed by the liver and red cells, and the only reliable way of assessing whether chronic copper accumulation is occurring is measurement of the liver copper concentration in a liver biopsy specimen. 6,7 Chronic, cumulative copper poisoning follows a benign clinical course until the binding sites of the liver are saturated, then acute hepatitis and hemolysis supervene. 7 However, the concept of using copper in the nebulizer reservoir in a concentration which would be bactericidal, or at least bacteriostatic, to Gramnegative bacilli but harmless to the patient, is an appealing one. Literature references to concentrations of copper in water which are bactericidal range from 1 to 10,000,000 to kill Pseudomonas aeruginosa in two hours" to 1 in 40 to kill Salmonella typhosa in ten minutes. 9 In our laboratories, the bactericidal action of cupric chloride against a recently isolated strain of Pseudomonas aeruginosa has been tested using the standard AOAC phenol coefficient method." After 15 minutes' exposure, no bactericidal action was detected at a copper concentration of 1,000 ppm. By prolonging the exposure time to 24 hours, bactericidal activity at a copper concentration of 100 ppm was clearly demonstrated. Such prolonged exposure is likely to be more relevant to the control of Pseudomonas contamination of inhalation therapy equipment. The concentration of 100 ppm of copper is, however, unacceptably high, because 500 ml of this solution nebulized each six hours would subject the patient to 200 mg of copper per day. This amount of copper ingested over a long period could lead to cumulative copper poisoning." Provided a fresh sterile solution were introduced initially into a sterilized nebulizer unit, lOa copper concentration of 10 ppm (0.0027 g CuCI 2.2H 20/100 ml) may be CHEST, VOL. 60, NO.2, AUGUST 1971
COMMUNICATIONS TO THE EDITOR
sufficiently high to inhibit bacterial proliferation while subjecting the patient to no more than 20 mg of copper per day. Further investigation of this problem is warranted to determine a minimum copper level which is both safe for the patient and a deterrent to bacterial growth. There would appear to be no hazard to the patient in the use of the copper pads to sterilize the expired air.
Jeanette Blomfield, M.Sc. and David C. Dorman, Ph.D," ·Children's Medical Research Foundation and the Institute of Pathology, Royal Alexandra Hospital for Children, Sydney, New South Wales, Australia. REFERENCES
1 Deane RS, Mills EL, Hamel AJ: Antibacterial action of copper in respiratory therapy apparatus. Chest 58: 373, 1970 2 Manzler AD: Copper, pH, and hemodialysis. Ann Intern Med 74:147,1971 3 Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia. A new complication of hemodialysis. Ann Intern Med 73:4~, 1970 4 Matter BJ, Pederson J, Psimenos G, et al: Lethal copper intoxication in hemodialysis, Trans Amer Soc Artif Int Organs 15:309, 1969 5 Blomfield J, MacMahon RA: Micro determination of plasma and erythrocyte copper by atomic absorption spectrophotometry. J Clin Path 22:136, 1969 6 Blomfield J, McPherson J, George CRP: Active uptake of copper and zinc during haemodialysis, Brit Med J 2:141, 1969 7 Blom6eld J, Dixon SR, McCredie DA: Potential hepatotoxicity of copper in recurrent hemodialysis. Arch Intern Med (in press) 8 Wilson GS, Miles AA: Principles of Bacteriology and Immunity, (5th Ed). London, Edward Arnold Ltd, Vol 1, 139, 1964 9 Lawrence CA, Block SS: Disinfection, Sterilization, and Preservation. Philadelphia, Lea & Febiger, 1968 10 Committee on Therapy: Cleaning and sterilization of inhalation equipment. Amer Rev Resp Dis 98:521, 1968
To the Editor:
Thank you for the opportunity to reply to the letter from Drs. Blomfield and Dorman. We would like to reply to the questions and concerns raised by their communication.
PulmoruzTy Infection Rate It should be emphasized that the average pulmonary infection rate of 6.59 percent! occurred with a single copper sponge in the large reservoir nebulizCHEST, VOL. 60, NO.2, AUGUST 1971
203
ere The drop to 1 percent or less followed the introduction of the Vermont copper bactericidal trap on the expired side of the ventilator circuit and closed system filling of the reservoir nebulizer.
CO 2 Content and pH of Nebulizer Water pH The pH of sterile water (Travenol) was measured immediately following its introduction to the reservoir nebulizer, and at various times during its period of use (24 hours). The range of pH was 5.86 to 7.97, average 6.81, and it should be noted that it did not fall during use.
CO 2 Levels As the reservoir nebulizer is part of a nonrebreathing ventilator circuit, it is exposed to the oxygen concentration driving the ventilator, and is not exposed to ambient air. There is no reason to suspect that the CO 2 content would rise. This was confirmed by analyzing samples with a PC02 electrode-the PC02 was zero. From these observations we cannot agree with the authors' suggestion that the rise in copper levels is due to either of these reasons, but would agree that the copper sponges should be thoroughly cleaned and washed free of acetic acid.
Copper Levels In our experience, the average patient receives 1500 ml of nebulized water every 24 hours; thus, the large inline nebulizer ( Bird) is filled three times. Samples of water were analyzed for their copper content from various sites in the ventilator circuit over 24 hours of use.
Inspired Limb of the Ventilator Circuit The range of copper levels found were from 7p.g/100 ml immediately following filling to 210ug percent after eight hours of use. Random samples during use showed an average concentration of 180p.g percent. Our normal practice is to change the large reservoir nebulizer and all parts distal to it every 24 hours! A nebulizer was deliberately not changed for 72 hours-the level at this time was 210p.g percent.
Expired Limb of the Ventilator Circuit It might be inferred from the authors' letter that all the copper is absorbed by the patient's lungs. A trap which was identical to the copper trap except that it was constructed from plastic was used to
202
to be a trend in these large groups, particularly in view of the more serious illness in our MINCA group as compared to the control group. The two groups were very similar as to sex distribution and average age. The number of patients with pneumonia, diabetes mellitus, and cancer treated in the MINCA unit during the five-month evaluation period was too small for adequate mortality comparisons. There was no statistical difference in the total hospital stay in the MINCA group compared to the control group. Health care activity rate is a measurement of total professional and nursing care per day, and was significantly greater for MINCA patients in eight of nine disease categories, compared to the controls. Edward I. Elisberg, M.D.o Highland Park, Illinois "Chairman, Department of Medicine, Highland Park Hospital; Assistant Professor of Medicine, Northwestern University Medical School, Chicago. REFERENCES
1 Jeffers WN: Acute beds only? Med Econ 45: 191, 1968 2 Listi SA: Constant care unit. Hospitals 44:41, 1970 3 Grace WJ, Yarvote PM: The intermediate coronary care unit-preliminary observations. Clin Res 17:579, 1969
The Controlled Use of Copper as an Antibacterial Agent in Respiratory Therapy Apparatus To the Editor:
A successful reduction in the incidence of pulmo. nary infection in patients on IPPB therapy by the continuing sterilization by copper of the nebulizer reservoir and effluent air has been achieved by Dr. Deane and co-workers 1 (Chest 58:373, October, .1970). However, the use of a 10 to 20 gram copper scouring pad in the reservoir introduces an unwarranted risk of copper poisoning to these patients, particularly to those on longterm. therapy. Although the reported level of copper in the nebulizer of 194 JA-g/100 ml would expose the patient to less than 4 mg of copper per day, any acidity in the water could very readily increase the dissolved copper to danger levels." Such acidity could derive from the local water source, from incomplete removal of the acetic acid used to clean the copper scouring pad or to sterilize the equipment, or from accumulation of carbon dioxide from ambient air. The latter possibility is suggested in
the observed increase in reservoir copper from 9.5 p.g/100 ml at four hours to 194 p.g/l00 ml at eight hours. Copper dissolved from a copper heat exchanger by acid water from an exhausted de ionizer has caused acute hemolytic and gastrointestinal episodes, at times fatal, in a number of patients undergoing hemodialysis. 3. 4 The moderately raised plasma total copper levels shown in the majority of Dr. Deane's patients on longterm IPPB therapy could be due to a harmless increase in the copper-containing protein, ceruloplasmin, because of infection or oral contraceptives, but could also be due to an increase of the free, potentially toxic, ionic copper of the plasma, which is transported by the albumen, and which normally ranges from 5 to 15 p.g/l00 mI. 5 Excessive amounts of this free copper are rapidly removed by the liver and red cells, and the only reliable way of assessing whether chronic copper accumulation is occurring is measurement of the liver copper concentration in a liver biopsy specimen. 6,7 Chronic, cumulative copper poisoning follows a benign clinical course until the binding sites of the liver are saturated, then acute hepatitis and hemolysis supervene. 7 However, the concept of using copper in the nebulizer reservoir in a concentration which would be bactericidal, or at least bacteriostatic, to Gramnegative bacilli but harmless to the patient, is an appealing one. Literature references to concentrations of copper in water which are bactericidal range from 1 to 10,000,000 to kill Pseudomonas aeruginosa in two hours" to 1 in 40 to kill Salmonella typhosa in ten minutes. 9 In our laboratories, the bactericidal action of cupric chloride against a recently isolated strain of Pseudomonas aeruginosa has been tested using the standard AOAC phenol coefficient method." After 15 minutes' exposure, no bactericidal action was detected at a copper concentration of 1,000 ppm. By prolonging the exposure time to 24 hours, bactericidal activity at a copper concentration of 100 ppm was clearly demonstrated. Such prolonged exposure is likely to be more relevant to the control of Pseudomonas contamination of inhalation therapy equipment. The concentration of 100 ppm of copper is, however, unacceptably high, because 500 ml of this solution nebulized each six hours would subject the patient to 200 mg of copper per day. This amount of copper ingested over a long period could lead to cumulative copper poisoning." Provided a fresh sterile solution were introduced initially into a sterilized nebulizer unit, lOa copper concentration of 10 ppm (0.0027 g CuCI 2.2H 20/100 ml) may be CHEST, VOL. 60, NO.2, AUGUST 1971
COMMUNICATIONS TO THE EDITOR
sufficiently high to inhibit bacterial proliferation while subjecting the patient to no more than 20 mg of copper per day. Further investigation of this problem is warranted to determine a minimum copper level which is both safe for the patient and a deterrent to bacterial growth. There would appear to be no hazard to the patient in the use of the copper pads to sterilize the expired air.
Jeanette Blomfield, M.Sc. and David C. Dorman, Ph.D," ·Children's Medical Research Foundation and the Institute of Pathology, Royal Alexandra Hospital for Children, Sydney, New South Wales, Australia. REFERENCES
1 Deane RS, Mills EL, Hamel AJ: Antibacterial action of copper in respiratory therapy apparatus. Chest 58: 373, 1970 2 Manzler AD: Copper, pH, and hemodialysis. Ann Intern Med 74:147,1971 3 Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia. A new complication of hemodialysis. Ann Intern Med 73:4~, 1970 4 Matter BJ, Pederson J, Psimenos G, et al: Lethal copper intoxication in hemodialysis, Trans Amer Soc Artif Int Organs 15:309, 1969 5 Blomfield J, MacMahon RA: Micro determination of plasma and erythrocyte copper by atomic absorption spectrophotometry. J Clin Path 22:136, 1969 6 Blomfield J, McPherson J, George CRP: Active uptake of copper and zinc during haemodialysis, Brit Med J 2:141, 1969 7 Blom6eld J, Dixon SR, McCredie DA: Potential hepatotoxicity of copper in recurrent hemodialysis. Arch Intern Med (in press) 8 Wilson GS, Miles AA: Principles of Bacteriology and Immunity, (5th Ed). London, Edward Arnold Ltd, Vol 1, 139, 1964 9 Lawrence CA, Block SS: Disinfection, Sterilization, and Preservation. Philadelphia, Lea & Febiger, 1968 10 Committee on Therapy: Cleaning and sterilization of inhalation equipment. Amer Rev Resp Dis 98:521, 1968
To the Editor:
Thank you for the opportunity to reply to the letter from Drs. Blomfield and Dorman. We would like to reply to the questions and concerns raised by their communication.
PulmoruzTy Infection Rate It should be emphasized that the average pulmonary infection rate of 6.59 percent! occurred with a single copper sponge in the large reservoir nebulizCHEST, VOL. 60, NO.2, AUGUST 1971
203
ere The drop to 1 percent or less followed the introduction of the Vermont copper bactericidal trap on the expired side of the ventilator circuit and closed system filling of the reservoir nebulizer.
CO 2 Content and pH of Nebulizer Water pH The pH of sterile water (Travenol) was measured immediately following its introduction to the reservoir nebulizer, and at various times during its period of use (24 hours). The range of pH was 5.86 to 7.97, average 6.81, and it should be noted that it did not fall during use.
CO 2 Levels As the reservoir nebulizer is part of a nonrebreathing ventilator circuit, it is exposed to the oxygen concentration driving the ventilator, and is not exposed to ambient air. There is no reason to suspect that the CO 2 content would rise. This was confirmed by analyzing samples with a PC02 electrode-the PC02 was zero. From these observations we cannot agree with the authors' suggestion that the rise in copper levels is due to either of these reasons, but would agree that the copper sponges should be thoroughly cleaned and washed free of acetic acid.
Copper Levels In our experience, the average patient receives 1500 ml of nebulized water every 24 hours; thus, the large inline nebulizer ( Bird) is filled three times. Samples of water were analyzed for their copper content from various sites in the ventilator circuit over 24 hours of use.
Inspired Limb of the Ventilator Circuit The range of copper levels found were from 7p.g/100 ml immediately following filling to 210ug percent after eight hours of use. Random samples during use showed an average concentration of 180p.g percent. Our normal practice is to change the large reservoir nebulizer and all parts distal to it every 24 hours! A nebulizer was deliberately not changed for 72 hours-the level at this time was 210p.g percent.
Expired Limb of the Ventilator Circuit It might be inferred from the authors' letter that all the copper is absorbed by the patient's lungs. A trap which was identical to the copper trap except that it was constructed from plastic was used to