European Journal of Cardiovascular Medicine

Healthcare personnel handling chemotherapeutic agents/ antineoplastic drugs are in danger of being exposed to such drugs at any stage of medication handling be it preparation, administration or disposal. A number of studies have found the presence of these drugs either in the urine or blood of the healthcare personnel involved directly/indirectly in handling these drugs.^1,2,3 Further as certified by various pharmacopoeias across the world, presence of these drugs beyond a limit in the blood/ urine of any person could be detrimental to their health.^4,5Reports of occupational exposure to chemotherapeutic drugs and their acute and reproductive effects on healthcare personnel directly or indirectly handling such drugs has been documented by various authors time and again.^6,7,8Hence,it is imperative for us to identify the source of contamination.^9,10

A number of organizations around the world have published a number of guidelines emphasizing on the importance of safe handling of chemotherapeutic/ antineoplastic agents.^11,12,13Studies have shown noncompliance to such guidelines. Recent European studies have shown that measurable levels of environmental contamination are present in the Healthcare setting.¹⁴ Drugs most commonly found are cyclophosphamide, ifosfamide, fluorouracil, methotrexate and doxorubicin.These drugs were found across the patient care areas despite these drugs being prepared within Biosafety cabinets.^15,16.

One of the most important areas of contamination is the environment (including the surfaces). Authors across the globe have also concluded that in addition to the environmental surfaces, the primary packaging of these drugs are also a potential source of contamination. M.hedmer et al. in their study conducted at Sweden found contamination on all surfaces after those surfaces being thoroughly cleaned every morning before taking in the first patient.¹⁷ This finding helped them reach to the conclusion that contamination occurred due to drug leakage during the working day. Connor et al. (1999) found considerable amounts of Ifosfamide and Cyclophosphamide in both the preparation and administration areas.¹⁸ They found the presence of these anitineoplastic agents on 75% of the drug preparation areas and in only 65% of the drug administration area.

It was only in 1980’s when class II Bio Safety Cabinets were first used for the preparation and handling of chemotherapeutic agents.^19,20 Use of these Bio Safety Cabinets was believed to be responsible for reducing occupational exposure to the chemotherapeutic agents. However, studies across the globe have demonstrated significant surface contamination even in healthcare settings where Bio Safety cabinets were being used. Connor et al. (2002) in their study reported no surface contamination when closed system device in a setting was used for the preparation / administration of the chemotherapeutic agent without using Biosafety cabinets for a year in a Swedish Hospital.²¹

The current study was conducted with the objective to ascertain the effectiveness of the Closed System Transfer device in reducing environmental contamination while reconstituting and administering the chemotherapeutic agents, to establish efficacy of CSTD in eliminating the contamination of drugs upon reconstitution of chemotherapeutic agents, allowing for optimization of vial usage leading to lower overall costs, to determine its ease of use and understand the cost implication of using CSTD for patients receiving chemotherapy in a healthcare setting where high volumes of chemotherapeutic agents are being handled without the use of a Biosafety cabinet.  Secondary objective of the study was to ascertain the perception of health care worker handling CSTD in terms of exposure to the chemotherapeutic agent and to give recommendations to help redesign the process of chemotherapy preparation and administration.

This prospective case-control study was conducted in the chemotherapeutic Chemotherapy Day care centerof a super-Speciality oncology centre over a period of one month, conducted for 50 reconstitutions of chemotherapeutic agents. The ward is having total 24 beds which have been divided into cubicles of 6 bed each as shown in the figure 1. The study was conducted in 2 cubicles of the ward. The study population were the nursing staff and resident doctors, handling chemotherapeutic agents in the designated cubicles selected for the study – intervention and control groups.

For Objective 1

Baseline observation of current reconstitution practices as well as evaluation of drug spillage while reconstituting by collecting swabs of surface (hand, table and wall) and testing.

For Objective 2

Microbiological drug contamination pre and post reconstitution of drug was tested by collecting aliquots of 0.5 ml – 1 ml from multidose vials of the five most commonly used chemotherapeutic drugs.

For Objective 3&4

Data was collected pre and post usage, using an structured, pre formed and standardized internally validated close ended questionnaire.

The study was conducted in two phases:

1^st Phase: for one week wherein baseline observation of current reconstitution practices as well as evaluation of drug spillage by collecting surface swipe swabs from 17 areas (hand, table and wall) were carried out. The processes at the Day Care center were mapped and studied. Surfaces examined were thoroughly decontaminated after collection of surface swabs using established cleaning protocols to remove hazardous drug residues. In addition, to ascertain spillage, a dark colored chart paper was placed on each surface and discolorations at the end of the day were noted.

2^nd Phase: was of three weeks duration, wherein training was imparted on usage of the device. Care was taken to ensure that the patients with similar treatment profile in the control phase availed treatment in two cubicles under study.

The cost analysis of usage of the deviceshall be done after ascertaining the minimum expenditure incurred in

• Preparing the drug: The number of vials used in the designated cubicle were counted and documented.
• Administering the drug: The number of medications administered as bolus or through the I.V line were accounted for and documented separately. The results for contamination, responses to the variables in the questionnaire were compiled, tabulated and reviewed. The data was analyzed using SPSS version 21.0.

The study was conducted in two phases: One was the pre intervention survey and the other was the post intervention survey.

The process mapped is as follows:

Patient gets admitted in the day care and is prescribed medication. Medicines dispensed are mostly provided by the centre as it is a government sponsored hospital and rest is brought by the patient. The drug is prepared in two areas in the day care ward. One is the treatment room (as provided by the hospital) and other is patient’s bed side (procured by the patient) with non-availability of bio-safety cabinets.

Drug preparation: After donning personal protective equipment (PPE), the reconstituted drug is withdrawn as per the prescribed dose in treatment room/ patient’s bedside for administration.

Drug Administration: The drugs are either administered as a bolus dose or as i.v. fluid infusions. Waste disposal is done as per the statutory guidelines.

Environmental contamination: The 17 areas where same in pre and post test evaluations. Surfaces examined were thoroughly decontaminated after surface swabs collection using established cleaning protocols that are known to remove hazardous drug residues.

The swipe test results from both the laboratories ascertained the fact that the phenomenon of environmental contamination was a fact at the Day care centre as shown in the table 2. It is seen that there was significant reduction in the value of contamination in almost all areas after use of CSTD. As per US Pharmacopoeia, all the drugs found in the swipe test contaminations are liable for human uptake above levels of 1 ng/cm².²² The results show that the level of contamination found in the control phase were as high as 4780 ng /cm²   to varied findings for different drugs in different areas. These values were seen to reduce in almost all areas and in some instances, they were even reduced to Beyond Detection Limits (BDL) after the use of CSTD. In the current scenario, where increasing weight-age is being given to worker safety, even the US FDA has approved the use of the device, even if the centre/ hospital has a Biosafety cabinet installed.

Table 1: Pre and Post swipe test results from Laboratory 1

Table 2: Pre and Post contamination results from Laboratory 2

The investigator at Lab. 2, interpreted the findings of cyclophosphamide contamination as huge. It was further stated that contamination was found in almost all areas and recommended to investigate the cleaning methods and tools being used, as reused cleaning tools may have accumulated contamination over time. e.g. towels/ mops. Also, as cross-contamination continues, it leads to non-preparation areas also being high on contamination.

Nurses Survey

The educational status of the participating nurses varied from an Auxiliary nurse Midwife to post graduate nurses as is depicted in Figure 1. 52.77 % nurses were having a work experience of more than five years.Time spent by the respondents for preparing chemotherapeutic agents ranged from 20 min. to 8 hours with an average of 3.5 hours per day, with maximum time as 12 hours. In the control phase, 75% of the respondents complained of having experienced symptoms such as headache, skin allergy, bitter taste in mouth, loss of appetite, hair fall, oral ulcers, burning in eyes, suffocation after preparing/administering chemotherapeutic agents. The respondents who did not experience these symptoms, were those ones who are in contact with chemotherapeutic agents for about 20 minutes to half an hour a day, with experience of < 6 six months in handling chemotherapeutic agents. Occurrence of chronic effects could not be ascertained as it was beyond the scope of the study.

Figure 1: Educational status of the participating nurses

In post CSTD usage phase, only the nurses who used the CSTD were the subjects from whom responses were collected All respondents found the system easy to use. 50% of nurses found the system to take extra time in addition to the normal procedure.

All participants found CSTD to be useful in the following parameters:

1. Reducing drug Spillage
2. Protect against drug splashes in eyes or skin
3. Recommended CSTD as safe, needleless, airtight and Leak-proof system
4. Training and use of BD Phaseal™ has raised awareness and knowledge of the safe handling practices of hazardous drugs

Cost effectiveness of the device:

CSTD components used for compounding and data was gathered for a total of 69 Patients. Details of units used for each reconstitution / patient are given in Table 5. A minimum of one component needs to be used in each patient and maximum of 3 each for the injector and connector components and seven of protectors depending on the treatment regime of the patient. Each component costs Rs. 100 making the average on per case to be Rs.600. However, the protector need not be used on a case-to-case basis, it is to be used on a single multidose vial and its usage is dependent on the number of vials being used in the centre. The injector has to be used on a case-to-case basis and is a single use device. However, one connector can be used per patient as all drugs can be infused using the same connector in the same patient.

Table 3 : Consumption of the different components of the CSTD

Use of this device has shown to increase the shelf life of the medications, thus useful in reducing wastage of drugs which becomes a cost saving measure.The savings which the study site could have based on the findings during the study for the most frequently used medications leading to maximum cost saving  have been illustrated in Figure 2.

Figure 2: Preventable Drug wastage

On further calculations of the cost implications, Rs.65,862 /- could be saved if the wastage of drugs was taken into consideration whereas Rs.67,220/- were spend on the use of the device during the duration of the study. The difference being of Rs.1,358/-. Further study is required to ascertain on the actual cost savings to the patient.

Drugs can escape in the environment during any one of the steps be it preparation, administration and disposal of drugs. Health hazards experienced amongst healthcare personnel exposed to chemotherapeutic agents is common knowledge. Exposures to chemotherapeutic agents can occur various routes be it the hands, airs, etc. The study was carried with the aim to determine the effectiveness of using a closed system device in reducing exposure. Contamination of all the drugs in the present study was found across all areas from where swipes were taken for analysis. Connor et al. (1999) & McDevitt et al. found the presence of contamination across all areas indicates that the risk of exposure to antineoplastic agents in the working environment is commonplace even with recommended precautions in place.^{18, 23}Hence, it is not surprising for the authors to find high levels of contamination in their study setting because of absence of Biosafety cabinets.

The swipe test results in the current study concluded that there was significant reduction in the value of contamination in almost all areas after use of CSTD. The results show that the level of contamination found in the control phase were as high as 4780 ng /cm²   to varied findings for different drugs in different areas. These values were seen to reduce in almost all areas and in some instances, they were even reduced to Beyond Detection Limits (BDL) after the use of CSTD. These findings are in sync with the finding of Sessink et al. who used the closed system device without a Biosafety cabinet to prepare the chemotherapeutic agents in a hospital in Sweden.¹⁵

Contamination was found in almost all areas under study and on studying the pattern in detail it was recommended to investigate the cleaning methods and tools being used, as reused cleaning tools may have accumulated contamination over time. e.g. towels/ mops. Also, as cross-contamination continues, it leads to non-preparation areas also being high on contamination. Connor et al. (2002) in their work also came to a similar finding where efficacy of cleaning practices in the area of study was held responsible for contamination.²¹

All the respondents in the present study found the system easy to use. However, 50% of the respondents  found the system to take extra time in comparison to the conventional procedure. Favier et al. (2011) in their study conducted at France has established the benefit of using a closed system device in protection of healthcare personnel handling hazardous drugs. Further the author also supports the finding of the current study where the duration of drug preparation and administration has not been impacted by the use of the device.²⁴

Limitations of the study as felt by the authors were that the wipe samples were collected by one person only, the infection control nurse, but there is no knowledge as to how the results of wipe samples may be affected when the same is taken by various people.The study was carried out over a short duration.Only a limited number of antineoplastic drugs were analyzed. The drugs chosen were the ones that were available as multidose vials.

The present study revealed that use of closed system transfer device has been instrumental in reduction of environment contamination in the setting of an Indian Hospital. However, long term monitoring is required to further ascertain the long term effects of using this device in Indian Settings.

Recommendations:

As per the guidelines prescribed by various agencies throughout the world namely ISOPP, ASHP, NIOSH, Preparation and administration of hazardous drugs/ Chemotherapeutic agents need to be done in confined safe environment, which is, use of a Biosafety cabinet along with CSTD. A Biosafety cabinet itself is not a completely safe solution as the hazard of exposure during drug spillage and drug preparation still exists.²⁵ A CSTD has been recommended as this device creates a vacuum while drug reconstitution and preparation thereby elimination the risk of drug exposure. In addition, the risk of needle stick injuries is also eliminated.

Proposed process (in event of non-availability of both a Bio safety cabinet and CSTD):

All chemotherapeutic medications should be prepared in a single earmarked area. The practice of preparing drugs in the patient care cubicle should be done away with. The HCW should document patient identification parameters on the drug vial in order to reuse the left-over medication for the same patient. In addition, staff for preparation and administration should be separate which would help reduce exposure of all HCW to the chemotherapeutic agent.Appropriate PPE to be used by the patient (such as face mask) and HCW.

Personnel Protective equipment: It is suggested that either the health care personnel continue to use the same gloves in double and change them after every reconstitution or the centre could consider procuring heavy duty gloves as recommended by international guidelines. All nursing personnel must ensure that while using face masks both their nostrils and mouth is covered to avoid intake in event of a splash.

Rotation of staff: It is recommended that staff involved in handling chemotherapeutic agents should be rotated on a regular basis so that the effect of being exposed to chemotherapeutic agents could be minimized.

Cleaning practices: If feasible the cleaning mops being used in this area may be changed on a daily basis. The sanitation personnel should be trained to wear PPE. .

Reducing wastage: Use of CSTD is shown to increase the shelf life of the drug after reconstitution. Hence, the centre could explore the feasibility of procuring higher volume multidose vials from the manufacturer thus reducing cost. Further use of higher volume vials shall also be instrumental in reducing the number of adapters to be used. Thereby reducing overall cost of the product.

Selective use of CSTD: CSTD device may be used in the most commonly used drugs such as cyclophosphamide, cisplatin, epirubicin, etoposide and doxorubicin which are available commercially as multidose vials.

Taking the probable risk of exposure of health care personnel to chemotherapeutic agents, it is essential for healthcare organizations to take measures which shall be instrumental in reducing this exposure substantially.Use of a closed system device may offer a solution to this problem and when used with other safe handling practices should make the environment safer for the health care worker.

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