Orthophthalaldehyde high level disinfectants are contraindicated for use with urological instruments such as cystoscopes due to anaphylaxis-like allergic reactions during surveillance of bladder cancer patients. Allergic reactions and mucosal injuries have also been reported following colonoscopy, laryngoscopy, and transesophageal echocardiography with devices disinfected using orthophthalaldehyde. Possibly these endoscopes were not adequately rinsed after disinfection by orthophthalaldehyde. We examined this possibility by means of a zone-of-inhibition test, and also a test to extract residues of orthophthalaldehyde with acetonitrile, from sections of endoscope insertion tube materials, to measure the presence of alkaline glutaraldehyde, or glutaraldehyde plus 20% w/w isopropanol, or ortho-phthalaldehyde that remained on the endoscope materials after exposure to these disinfectants followed by a series of rinses in water, or by aeration overnight. Zones of any size indicated the disinfectant had not been rinsed away from the endoscope material. There were no zones of inhibition surrounding endoscope materials soaked in glutaraldehyde or glutaraldehyde plus isopropanol after three serial water rinses according to manufacturers' rinsing directions. The endoscope material soaked in orthophthalaldehyde produced zones of inhibition even after fifteen serial rinses with water. Orthophthalaldehyde was extracted from the rinsed endoscope material by acetonitrile. These data, and other information, indicate that the high level disinfectant orthophthalaldehyde, also known as 1,2-benzene dialdehyde, cannot be rinsed away from flexible endoscope material with any practical number of rinses with water, or by drying overnight.
There are many references in the scientific literature noting anaphylactic shock reactions for patients examined with cystoscopes [
While there are label warnings against the use of OPA high level disinfectants for the disinfection of cystoscopes, and special instructions for ensheathing TEE probes, there is no warning or contraindication for the use of OPA to disinfect laryngoscopes or colonoscopes, for which there are peer-reviewed reports of serious allergic reactions. The materials of insertion tubes for all manufacturers of cystoscopes, laryngoscopes, colonoscopes, bronchoscopes, and gastroscopes, are all constructed using the same or similar flexible polymeric material. However, there is no contraindication on the OPA labels that it should not be used to disinfect laryngoscopes, bronchoscopes, gastroscopes, or colonoscopes, which might be taken to imply that these other medical devices can be adequately rinsed to remove the OPA residues, while cystoscopes and TEE probes cannot. The investigations of this paper were carried out to determine how many rinses are necessary to remove OPA from endoscope insertion tube materials, and the results indicated surprisingly that OPA adsorbs to the endoscope materials and cannot be rinsed away with any practical or even greatly excessive numbers of rinses with water. The test methods and results of this paper are the first to identify by observed zones of inhibition and chemical extraction that OPA adheres or adsorbs to the materials of endoscopes. The adverse clinical reactions reported from endoscopes and TEE probes disinfected with OPA are not the result of poor or insufficient rinsing procedures. If residues of OPA remain on endoscopes, cannot be rinsed away with any practical number of rinses, and can be transferred to patients, then some consideration should be given to the nature and potential toxicity of the OPA chemical, which is 1, 2-benzene dialdehyde, that is, a modified benzene compound. Possibly the warnings regarding OPA should be extended to other medical devices that remain in place for a length of time sufficient to produce mucosal injury, or might be used for examinations and reexaminations of the esophagus, stomach, colon, bronchioles, and lungs; or possibly some OPA removal technique such as rinsing in an organic solvent should be developed.
Endoscope insertion tube parts representing many models of flexible endoscopes were obtained new from Endoscope Repair, Inc., and Olympus America, Inc. Endoscope insertion tubes (colonoscope part no. 417900, Olympus America Inc., and Pentax-compatible part no. EG-2900/2901), and endoscope bending rubbers made of Viton, silicone, and polyvinylchloride (obtained from Endoscope Repair, Inc.) and bending rubber “A” (obtained from Olympus America Inc.), all of which are parts of endoscopes that contact disinfectants and the patient, were stripped of any metal parts, and then cut into approximately 2.0 cm × 1.0 cm sections. These sections of endoscope materials were soaked in 2.4% w/w alkaline glutaraldehyde Solution (GA) (Cidex Activated Dialdehyde Solution, Advanced Sterilization Products, Irvine, CA); 3.4% w/w GA plus 20% w/w isopropanol Solution (GA-IPA) (Aldahol High Level Disinfectant, Healthpoint, LTD, Fort Worth, TX); or 0.55% w/w orthophthalaldehyde Solution (OPA) (Cidex OPA, Advanced Sterilization Products, Irvine, CA) for 10.0 min at 20°C for GA-IPA, and 25°C for GA, and OPA, the label temperature directions for these disinfectants. The endoscope insertion tube materials were then rinsed multiple times in 100 mL of filtered tap water per rinse. The pieces were soaked and agitated in each rinse for 1.0 min, and then moved from rinse to rinse with sterile stainless steel forceps. These rinses for 2.0 cm2 sections of endoscope insertion tube materials were proportionally similar in volume and rinse time to the rinses directed by the disinfectant manufacturers for whole endoscopes.
To determine how much disinfectant might remain on a complete endoscope before rinsing, an intact Olympus gastroscope was immersed in GA-IPA for 10.0 min, removed from the disinfectant, and the interior channels were then drained and purged with air. The endoscope was weighed before and after exposure to the disinfectant. About 20.0 g (20.0 mL) of disinfectant remained on a gastroscope as ready to be rinsed. The small sections of endoscope material were similarly weighed before and after exposure to the disinfectants to determine that about 0.2 g (mL) of disinfectant remained on these sections. This information was used to calculate the total dilution factor following three two-gallon rinses of an endoscope, or various numbers of rinses with 100 mL of water for the small sections.
A culture of
Variations of this test using Viton bending rubber (the most commonly used bending rubber) and insertion tube material included increasing the numbers of rinses up to fifteen 100 mL rinses, multiple exposures to the test disinfectants up to five 10.0 min exposures per day, various post rinse drying times, and tests of the effects of a final wipe with isopropanol.
As an additional method to confirm that the ZOI were the result of OPA, a 2.0 cm × 1.0 cm section of Olympus colonoscope insertion tube was soaked in OPA for 10.0 min at ambient temperature, followed by three rinses in 100 mL of water per rinse. The soaked and rinsed section was then placed into 5.0 mL of acetonitrile (Sigma-Aldrich) in a 20 mL glass vial and agitated on a vortex mixer for 1.0 min to extract the OPA. This procedure was repeated with an identical section of insertion tube that had been rinsed with water and not soaked in OPA. The insertion tube sections were removed from the vials, and acetonitrile extractions, along with a sample of OPA were analyzed in a high performance liquid chromatography (HPLC) machine. The HPLC analysis of acetonitrile from the control section not soaked in OPA produced no signal on the chromatogram, while the analysis of the section soaked in OPA gave the same signal as OPA itself.
Table
Zones of Inhibition (ZOI) of
Endoscope material | GA @ 25°C or GA-IPA @ 20°C | OPA @ 25°C | ||
Three or seven rinses | Three rinses | Seven rinses | Fifteen rinses | |
Viton | ||||
Silicone | ||||
PVC | ||||
Rubber A | ||||
Insertion tube |
Table
Zones of Inhibition (ZOI) of
Endoscope material | GA @ 25°C or GA-IPA @ 20°C | OPA @25°C | ||
One 10 min exposure | Five 10 min exposures | One 10 min exposure | Five 10 min exposures | |
Viton bending rubber | ||||
Colonoscope insertion tube |
Table
Zones of Inhibition (ZOI) of
Drying times | OPA @ 25°C | |
Viton bending rubber | Colonoscope insertion tube | |
Not dried | ||
1.0 hr | ||
2.0 hrs | ||
6.0 hrs | ||
Overnight |
Table
Zones of Inhibition (ZOI) of
Endoscope material | OPA @ 25°C | |
1 day | 2 days | |
5 exposures, 3 water rinses, and overnight drying | 5 exposures, 3 water rinses, and overnight drying | |
Viton | ||
Insertion tube |
A test was done to try to remove OPA from the insertion tube material by wiping the insertion tube with a cotton ball soaked in 75% isopropanol, and then drying for 15 min, or wiping the insertion tube material with 99.9% acetonitrile or 3% hydrogen peroxide (solvents for OPA). There was no reduction in the size of the ZOI following a wipe with isopropanol. Acetonitrile was able to wipe the OPA away from the Viton endoscope material, but not from the insertion tube material. Hydrogen peroxide was not able to remove the OPA from either the Viton material or the insertion tube material. There were no zones of inhibition around the Viton or the insertion tube material wiped with acetonitrile or hydrogen peroxide. These results are shown in Table
Zones of Inhibition (ZOI) of the growth of
Endoscope material | OPA | Acetonitrile | 3% hydrogen peroxide | ||
Three 10 min exposures/rinsesa | Three 10 min OPA exposures/rinsesa, Wipe/rinsesb | Wipe/ rinsesb | Three 10 min OPA exposures/rinsesa, Wipe/rinsesb | Wipe/ rinsesb | |
Viton | |||||
Insertion tube |
a Inbetween each 10 minutes OPA soak materials were rinsed three times with 100 mL of tap water.
b After wiping with acetonitrile or hydrogen peroxide materials were rinsed three times with 100 mL of tap water.
Figure
Typical zone of inhibition or no zone of inhibition on agar surfaces with a lawn of
There have been many reports in the scientific literature, some as referenced in this paper, of mucosal injuries and serious allergic reactions of patients treated with endoscopes disinfected with OPA and rinsed with water. The question is are these events happening because the endoscopes and TEE probes are not being adequately rinsed with water, or for some other reason such as the OPA adsorbs to the polymeric material of transesophageal echo probes and the insertion tubes of flexible endoscopes and cannot be rinsed away? Orthophthalaldehyde, glutaraldehyde, and glutaraldehyde antimicrobially enhanced by combination with isopropanol [
The rinsing directions for Cidex OPA are to rinse three times in 2.0 gal of water (7570 mL) per rinse. Assuming the endoscopes carry a residue of about 20 mL of disinfectant after soaking in a disinfectant, measured as described above in the methods section, the dilution factor is 378 for one rinse (7570 mL ÷ 20 mL), or about 54 × 106 for three rinses.
The small sections tested each carry about 0.2 mL of disinfectant solution. When rinsed in 100 mL of water, that is a 500-fold dilution of the disinfectant per rinse. Three such rinses give a dilution factor of 125 × 106, which is similar or in excess of rinsing an entire endoscope in two gallons of water three times. Seven rinses of the small sections of insertion tube material in 100 mL of water per rinse (100 mL ÷ 0.2 mL) is a dilution factor of about 7.5 × 1018, and fifteen rinses is about 3.05 × 1040, a huge dilution factor. Even after seven or fifteen serial rinses these insertion tube materials soaked in OPA, with the exception of bending rubber “A,” gave zones of inhibition indicating there was still OPA on these insertion tubes and bending rubber materials. The OPA is not rinsing away from the endoscope insertion tube materials. The OPA is building up on the materials with each successive exposure, and the OPA is not evaporating from the materials in any practical drying time relative to clinical demands to reuse the disinfected endoscopes several times per day, or even overnight.
In terms of rinsability, all of the chemicals of the three high level disinfectants tested reacted as would be expected from the physical characteristics of their solubility in water and their vapor pressures (ability to evaporate). Both GA and IPA are very soluble in water, infinitely so with IPA solubility in water, and 64 g of GA are soluble in 100 mL of water. These two chemicals consistently rinsed away from the endoscope materials with three rinses in water and did not build up on the endoscope material surfaces after repeated exposure and rinses.
OPA has a very low solubility in water at 0.60 g per 100 mL of water, and the solubility of OPA in alcohol is not much greater at 11 g/100 mL of alcohol (not specified). The endoscope surfaces exposed to OPA and wiped with isopropanol still gave zones of inhibition in these tests. GA and IPA have high vapor pressures and would be expected to slowly evaporate away from the endoscope surfaces even if they were not rinsed away with water. OPA has a very low vapor pressure of 0.0052 mm Hg at 21°C, which explains why it has a more tolerable odor than GA, and also explains why it does not evaporate from the endoscope surfaces drying overnight.
The standard method to measure that disinfectants can be rinsed away from medical equipment is to rinse the equipment in water and then measure the water for the presence of the disinfectant. After some series of rinses, including overnight extractions, the concentration of the disinfectant in the rinse water should be below any known levels of toxicity. However, if the disinfectant adsorbs to the medical instrument, then the disinfectant, or some concentration of the disinfectant, will not be in the rinse water to be measured. That is what we think is happening with measurements for residues of OPA. The manufacturer, regulatory agencies, and clinicians might not expect or look for such a scenario where the OPA is adsorbed to the endoscope material and is not dissolved in the rinse water, and thus not detectable in rinse water by ordinary methods.
We believe the body of evidence as listed here indicates that OPA adsorbs to the polymeric materials of endoscopes and other medical devices and cannot be rinsed away. (1) There are numerous reports in the scientific literature of mucosal injuries, and allergic reactions in patients exposed to equipment disinfected with OPA (cited in the introduction), (2) TEE probes, as disinfected with OPA and rinsed, must be placed into a protective cover before used with patients. (3) Animal toxicity studies [
What is different about cystoscopes from other endoscopes such as bronchoscopes, gastroscopes, colonoscopes, and laryngoscopes? The flexible polymeric construction materials of all of these endoscopes are similar. Cystoscopes as used to monitor bladder cancer are introduced into the body more frequently than other endoscopes, possibly sensitizing the body with the first introduction of OPA residues, and the body reacts to the allergen with additional examinations.
We encourage other scientists to repeat and expand on our studies of the rinsability of OPA. Possibly insertion tubes can be ensheathed to prevent contact of the mucous membranes with OPA disinfected insertion tubes in the same manner as with TEE probes Possibly some system of rinsing the endoscopes with such organic solvents as acetonitrile or hydrogen peroxide [
Norman Miner discloses that he is the inventor of Aldahol High Level Disinfectant, with a royalty interest. The studies of this paper were funded entirely by MicroChem Laboratory.