Clinical Therapeutics/Volume 36, Number 3, 2014
Administration of Anticancer Drugs: Exposure in Hospital Nurses Catherine Rioufol, PharmD, PhD1,2; Florence Ranchon, PharmD, PhD1,2; Ve´rane Schwiertz, PharmD2; Nicolas Vantard, PharmD2; Elsa Joue, PharmD2; Chloe´ Gourc, PharmD2; Noe´mie Gauthier, PharmD2; Marie Gabrielle Guedat, PharmD2; Gilles Salles, MD, PhD3; Pierre-Jean Souquet, MD4; Bertrand Favier, PharmD, PhD5; Laurence Gilles, PharmD5; Gilles Freyer, MD, PhD1,6; Benoıˆt You, MD, PhD1,6; ˆme Guitton, PharmD, PhD7 Ve´ronique Trillet-Lenoir, MD, PhD1,6; and Je´ro 1
University Claude Bernard Lyon, Lyon, France; 2Hospices Civils de Lyon, Groupement Hospitalier Sud, Clinical Oncology Pharmacy Department, Lyon, France; 3Hospices Civils de Lyon, Groupement Hospitalier Sud, Department of Haematology-University Claude Bernard, Lyon, France; 4Hospices Civils de Lyon, Groupement Hospitalier Sud, Department of Pneumology, Lyon, France; 5Centre Le´on Be´rard, Pharmacy Department, Lyon, France; 6Hospices Civils de Lyon, Groupement Hospitalier Sud, Department of Oncology, Lyon, France; and 7 Hospices Civils de Lyon, Groupement Hospitalier Sud, Chemotherapy Targeting in Oncology LaboratoryUniversity Claude Bernard Lyon, Faculty of Pharmacy, Toxicology Laboratory, Lyon, France ABSTRACT Background: Even though anticancer drugs are prepared in dedicated pharmaceutical units, nurses remain exposed to cytotoxic agents during administration to patients. Objective: The aim of this study was to assess this occupational exposure during the intravenous line– purging procedure at the patient’s bedside before administration in oncology departments. Methods: This prospective study was conducted over a 4-week period in the hematology and oncology departments at a university hospital. Amounts of doxorubicin and cyclophosphamide on the surface of nurses’ gloves were measured after the intravenous line purge of the infusion bag and the connection to the patient. For this purpose, gloves were washed with sterile water, following a validated procedure. Quantification of the 2 drugs into the water was performed using LC-MS/MS. Results: After 59 chemotherapy administrations, 30.5% of gloves were contaminated. Despite extremely low volumes of contamination (0.08–6.28 mL), amounts collected ranged from 190 to 2500 ng per pair of gloves that tested positive for doxorubicin (median, 1600 ng) and from 130 to 32,600 ng with cyclophosphamide (median, 2700 ng). Conclusions: The intravenous line purge preceding antineoplastic infusion bag administration is a potential source of contamination in nurses. Contaminations
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appear to be invisible but frequent (in 430% of cases). Therefore, intravenous line purging performed under appropriately safe conditions should be mandated in pharmaceutical units dedicated to injectable-drug preparation. This measure should be included as a standard hospital practice as a matter of urgency. (Clin Ther. 2014;36:401–407) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: antineoplastic, intravenous line purge, nurses, occupational exposure.
INTRODUCTION Aside from their curative effects, the widespread use of antineoplastic agents in the treatment of cancer has led to an increased concern of handling these drugs by the pharmacy team, nurses, and physicians because of their potential carcinogenic, mutagenic, and/or teratogenic effects in humans.1 During the past 20 years, safety standards have been issued to protect health care workers.2,3 In chemotherapy preparation, one of the first measures of preventing exposure in health care workers is to Accepted for publication January 26, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.01.016 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
401
Clinical Therapeutics centralize the preparation of cytotoxic drugs in pharmaceutical-preparation units, using specific guidelines, appropriate organizational measures, and specialized technical equipment, such as vertical laminar airflow safety hoods, or isolators, and protective clothing, including double pairs of gloves. For the administration step, gloves must be worn by nurses at all times when hazardous drugs are being handled. Although these guidelines are advanced to reduce workers’ exposure, recent studies have shown that recommendations were not always applied4–6 and that workplace contamination4,5,7–10 and occupational exposure have decreased but are still present. Worker exposures have been assessed by studies of biological markers. Cytogenetic effects, such as mutagenic activity in urine, micronucleus induction, chromosomal aberrations, and sister-chromatid exchanges, were reported.6,11–13 More recently, early DNA damage revealed with single-cell gel electrophoresis (CometAssay, Trevigen Inc, Gaithersburg, Maryland) were shown in health care workers handling antineoplastic drugs.4,6,9,13–16 Moreover, potential various acute (short-term) and chronic (long-term, eg, cancer) effects of residual exposure to hazardous drugs have been described in several epidemiologic studies.17–20 Although both the pharmacy team and nurses were regularly handling antineoplastic drugs, studies showed lower frequencies of genetic damage in pharmacists versus nurses,4,11,16 which could be explained by greater protective measures applied by pharmacists versus nurses, for whom gloves were the only protective measure employed.11 The procedure of purging the line with antineoplastic solution by nurses just before infusion-bag administration to patients was identified as a potential source of contamination, as has been the aerosolization or spilling of anticancer drugs. This route of contamination has been quantified in only 1 study.10 The procedure of purging the line with saline solution during chemotherapy preparation in the centralized pharmacy unit could be a solution to avoiding nurses’ exposure. However, for economic reasons (because of the necessary purchase of supplementary intermediate medical devices), this procedure is not applied in some hospitals. The aim of the present study was to assess occupational exposure in nurses during the intravenous line–purging procedure at the patient’s bedside before administration of antineoplastic infusion prepared by the pharmacy. According to the results, this study could be a major argument for hospital decision makers to change practices.
402
MATERIALS AND METHODS Study Design This prospective study was conducted in a 1200bed teaching hospital specializing in cancer patients’ care in France. Antineoplastic-infusion bags were prepared in the centralized pharmaceutical preparation unit under laminar vertical air-flow safety hoods. During the chemotherapy-preparation step, pharmacy technicians wore protective clothing, nursing caps, safety glasses, masks, and a double pair of gloves. The pharmaceutical-preparation procedures do not include the purging-line step, which is realized at the time of the administration by the nurse. At the end of the preparation step, the chemotherapy-infusion bag is packed in a sterile field under the hood and placed in a disinfected plastic bag outside the hood by the pharmacy technician, limiting chemotherapeutic contamination on the plastic bag. Then the preparation is transported from pharmacy to the day care unit in a box intended for hazardous drugs.
Nurse Recruitment Fifteen voluntary nurses (only women) from a hematology and oncology day care unit were involved in the study. These nurses are usually involved in antineoplastic-drug administration; 100% had 42 years of experience. The day hospital performs up to 30 drug administrations per day. Before administration, the nurse inserts the spike of the line into the tubing port of the infusion bag containing the antineoplastic preparation. The intravenous line (Eurofix, Braun Laboratories, Pasadena, California) is then purged with the cytotoxic solution at the patient’s bedside. An integrated end-line hydrophobic filter stopped the solution before expulsion from the set. Nurses were informed about the aim and the procedures of the study. Informed consent was signed by all participating subjects.
Glove Contamination and Sampling Two common cytotoxic drugs, doxorubicin and cyclophosphamide, were identified and quantified on the surfaces of the nurses’ gloves after administration to the patient. A total of 60 infusion bags were selected for the 4-week period of the study. For each selected infusion bag, 1 pair of nonsterile gloves was worn by the nurse before the line was purged and connected to the patient. At the end of the procedure, potential traces of antineoplastic drug on the surface
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Figure. Immersion of the nurse’s gloved hands in 100 mL of sterile water for injection (after connecting the infusion bag).
of the gloves were collected using an adapted procedure developed by Gilles et al.10,21 After connecting the infusion bag to the patient, nurses immersed their 2 gloved hands into a single-use, open plastic box (28 21 5 cm) containing 100 mL of sterile water for injection and carried out a 1-minute standardized friction of the 2 gloved hands. Six steps of 10 seconds each were implemented (Figure): friction of the (1) fingers; (2) palms; (3) back of the hands; and between the fingers of the (4) right and (5) left hands; and (6) circular friction of both hands in the solution. Then sterile water for injection was collected in 100-mL glass vials, shaken, and aliquoted in 3-mL glass tubes. Samples were stored at –201C until assay.
Doxorubicin and Cyclophosphamide Quantification Quantification of doxorubicin and cyclophosphamide was performed by LC-MS/MS (Quantum-Ultra, Thermo Fisher Scientific Inc, Rochester, New York). The standards of doxorubicin, daunorubicin, ifosfamide, and cyclophosphamide were supplied from Sigma (St. Quentin Falavier, France). Stock solutions of the 4 compounds were prepared in methanol at a concentration of 1 mg/mL and stored at 41C. These solutions were then diluted with water to yield a series of spiking standard solutions. Doxorubicin and cyclophosphamide were added to water to yield final concentrations from 1 to 1000 ng/mL, corresponding to the calibration curves. Daunorubicin and ifosfamide were used as internal standards for doxorubicin and
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cyclophosphamide, respectively. An internal standard is a compound structurally close to the analyte. A known quantity of standard is added to the unknown before any manipulations; thus, the ratio of standard to analyte remains constant and allows for obtaining more accurate results. For cyclophosphamide, chromatographic separation was performed on a Hypersil Gold 3-mm (150 2.1-mm) analytical column (Thermo Fisher). The mobile phase was a solution of water/formic acid at 0.1% (vol/vol) (phase A) and acetonitrile/formic acid at 0.1% (vol/vol) (phase B). For doxorubicin, chromatographic separation was performed on an Atlantis Hilic 3-mm (150 2.1-mm) analytical column (Waters Corporation, Milford, Massachusetts). The mobile phase consisted of an acetate ammonium buffer at pH 5 (phase A) and acetonitrile (phase B). In both cases, the mobile phase was delivered through the column (temperature maintained at 301C) at a flow rate of 200 mL/min. The mass spectrometer was operated in positive ion mode with electrospray source. For the quantification of doxorubicin and cyclophosphamide, the transitions m/z 544.2 361.0 (doxorubicin) and m/z 261.0 - 140.0 (cyclophosphamide) were monitored using the selected reaction monitoring. Peak area ratios of doxorubicin and cyclophosphamide to the respective internal standard measured at each nominal concentration were used to construct weighted (1/concentration) least-squares linear regression curves. The samples, previously frozen, were brought to room temperature and well-vortexed, and an appropriate volume of a solution of internal standard was added and 10 mL of the mixture was injected into the LC-MS/MS apparatus. The lower limits of quantification of doxorubicin and cyclophosphamide were each 1 ng/mL.
Calculation of the Amount of Drugs Present on the Surfaces of Gloves The concentration of each drug present in the samples was measured from calibration curves (from 1 to 1000 ng/mL). The quantities of both compounds on the surfaces of pairs of gloves were determined by multiplying the concentration measured by 100 (corresponding to the volume of water used for washing the gloves). The concentration of the compound present in the infusion administered to the patient and the quantity measured on the gloves were known, and the volume of infusion leading to the contamination was calculated.
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Table. Correspondence between concentration of anticancer drug in infusion bag, amount of drug and volume of cytotoxic solution collected per pair of contaminated gloves. Doxorubicin CIB (mg/mL)
Cyclophosphamide
QMG (mg)
Volume of contamination (mL)
0.50 2.3 1.6 73 2.5 0.19
380 1000 410 860 1000 350
Mean (1) (SD)
CIB (mg/mL)
QMG (mg)
Volume of contamination (mL)
1.32 2.30 3.90 84.88 (*) 2.50 0.54
4500 3960 5190 4500 5130 5190 4290 6000 5700 3000 2920 6000 1690
2.5 22.9 32.6 1.7 1.2 0.8 2.7 3.0 1.0 4.0 7.1 11.9 0.13
0.55 5.78 6.28 0.38 0.23 0.15 0.63 0.5 0.17 1.33 2.43 1.98 0.08
2.11 (1.27)
Mean (SD)
1.58 (⫾2.11)
CIB ¼ Concentration inside the infusion bag administered to the patient (mg/mL); QMG ¼ Quantity measured on gloves (mg); Volume of contamination (mL) ¼ (QMG/CIB) x 1000. * the mean excludes the outlying value marked
Statistical Analysis Descriptive analyses were realized by χ2 test, and P o 0.05 was considered as statistically significant.
RESULTS Overall, 60 samples were analyzed from 33 administrations of doxorubicin (100-mL infusion bags) and 27 administrations of cyclophosphamide (250-mL infusion bags). A total of 19 samples were positive; 1 result was considered as an outlier and was not included in the analysis. Gloves appeared to have been contaminated during the purge before the administration of the anticancer drugs in 30.5% of cases (18/59). Except for the outlier, 18 samples (30.5%) were positive, that is, 5 samples of doxorubicin (16% of doxorubicin preparations) and 13 samples of cyclophosphamide (48% of cyclophosphamide preparations). The frequency of contamination was greater with the 250-mL infusion bags of cyclophosphamide versus
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the 100-mL infusion bags of doxorubicin (P ¼ 0.007 [χ2 test]). The drug amounts collected on positive gloves ranged from 0.19 to 2.5 mg per glove pair with doxorubicin (median, 1.6 mg) and from 0.13 to 32.6 mg with cyclophosphamide (median, 2.7 mg). From the whole data, the average volume of contamination was calculated as 1.73 mL per pair of positive gloves. Complete data are shown in the Table.
DISCUSSION Although safety standards for cytotoxic drug handling have considerably been improved over the past 2 decades, workplace contamination and occupational exposure are still reported, which is a particularly worrying issue for all hospital staff specializing in oncology.22 Indeed, workplace contamination was still recently reported in oncology wards including both day-care
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C. Rioufol et al. and inpatient units.9,16 Correlation between the amount of drugs handled and the extent of surface contamination remains controversial, highlighting the necessity of systematic safety procedures.5,8,10 This concern has been urged by recent studies in which novel abnormalities, such as early DNA damage, were detected in health care workers handling antineoplastic drugs.9,12,23 Moreover, the use of personal protective equipment (ie, gloves and masks) decreased, but did not prevent, primary DNA damage.4,12 These findings were expected given the well-known permeability of gloves to cytotoxic agents.24 Even though anticancer drugs were prepared by the pharmaceutical team, contamination was detected in oncology wards, particularly in administration areas.9,11,16 Nurses seem to be less at risk for aerosol inhalation than through other means of exposure, such as direct skin contact with contaminated intravenous tubing, or patients’ excreta with hand-to-mouth contact.25 Gilles et al21 first investigated the intravenousline purge preceding infusion-bag administration and confirmed that this step was a potential source of contamination in nurses. The formation of aerosolized cytotoxic solution was demonstrated, confirming potential exposure. In agreement with Gilles et al, the present study demonstrated that contact between droplets of cytotoxic solution and gloves occurred during the purge procedure, leading to exposure in nurses. The high observed rate of glove contamination (430%) highlights strikingly substantial exposure occurring during the intravenous-line purge, even though the infusion bags had been prepared in the centralized pharmaceutical-preparation department. Because no "safe" occupational-exposure limit exists, the amount of antineoplastic contamination should be kept as low as possible. The present study reported a high rate of glove contamination, but with a low volume (ranging from 0.08–6.28 mL of cytotoxic solution, except for 1 outlier), and positive amounts of cytotoxic drugs (medians, 1600 ng [doxorubicin] and 2700 ng [cyclophosphamide]). The corresponding average amounts were in line with those collected in a previous study detecting 5fluorouracil (10,800 ng).21 Larger infusion-bag volumes of cyclophosphamide (250 mL) were correlated with more frequent contamination, likely suggesting the difficulty in handling large bags of cytotoxic preparations. Correlation with other, larger infusionbag volumes (eg, 500 or 1000 mL) remains to be
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confirmed using the same antineoplastic to avoid confounding factors. Such results not only confirm the necessity of wearing protective gloves during administration but also further demonstrate that the pharmaceuticalpreparation process should be extended to intravenous-line purging, as strongly suggested by Fransman et al.7 Many purge systems are available and have to be tested and adjusted to hospitals’ standard practices. These efforts are all the more justified as new drugs with unknown long-term effects are developed. These drugs involve chemicals with different structures, origins, and activities, constituting a vast heterogeneous class of compounds such as immunotherapy (ie, monoclonal antibodies) and cell and gene therapy (ie, vaccine). In the face of such uncertainties, vigilance needs heightening to protect staff against repetition of past bad experiences.
Study Limitations The present study focused only on the contamination of the gloves, without assessment of potential clinical effects in nurses. The limitations of this study include the small sample size (limited to 60 preparations) in only 1 hospital. Work practices, techniques, and experience in nurses may influence these results and have to be investigated. The use of a limited number of marker compounds to evaluate exposure could be limitative.
CONCLUSIONS Despite several guidelines and safety recommendations for anticancer-drug handling, including the use of protective equipment and the preparation of injectable anticancer drugs by a dedicated pharmaceutical unit, significant trace amounts of these agents were found on nurses’ gloves, with potential genotoxic risk. The intravenous-line purge preceding antineoplastic infusion–bag administration is a potential source of exposure in nurses. Invisible and frequent (in 430% of cases) contamination with significant amounts of cytotoxic drugs may lead to potential serious consequences. Adapted strategies to prevent such exposure should be developed to reduce the risk for contamination among exposed workers. The mandatory intravenous line purge under appropriately safe conditions in pharmaceutical units dedicated to injectable-drug preparation should be considered as
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Clinical Therapeutics standard hospital practice. Finally, health care workers’ monitoring should be routinely performed to reduce occupational exposure.
11.
ACKNOWLEDGMENTS The authors acknowledge the medical, pharmaceutical, and nursing teams at the Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
12.
13.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.
14.
REFERENCES 1. International Agency for Research on Cancer (IARC). Agents classified by the IARC monographs. http://monographs.iarc. fr/ENG/Classification/. Accessed December 1, 2013. 2. Department of Health and Human Services (DHHS), National Institute For Occupational Safety and Health (NIOSH). Preventing occupational exposure to antineoplastic and other hazardous drugs in Healthcare Settings. DHHS (NIOSH) publication no. 2004-165. http://www. cdc.gov/niosh/docs/2004-165/. Accessed February 3, 2014. 3. Chaffee BW, Armitstead JA, Benjamin BE, et al. Guidelines for the safe handling of hazardous drugs: consensus recommendations. Am J Health Syst Pharm. 2010;67:1545– 1546. 4. Villarini M, Dominici L, Piccinini R, et al. Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs. Mutagenesis. 2011;26:359–369. 5. Kopp B, Schierl R, Nowak D. Evaluation of working practices and surface contamination with antineoplastic drugs in outpatient oncology health care settings. Int Arch Occup Environ Health. 2013;86:47–55. 6. Rekhadevi PV, Sailaja N, Chandrasekhar M, et al. Genotoxicity assessment in oncology nurses handling antineoplastic drugs. Mutagenesis. 2007;22:395–401. 7. Fransman W, Peelen S, Hilhorst S, et al. A pooled analysis to study trends in exposure to antineoplastic drugs among nurses. Ann Occup Hyg. 2007;51:231–239. 8. Sottani C, Porro B, Imbriani M, Minoia C. Occupational exposure to antineoplastic drugs in four Italian health care settings. Toxicol Lett. 2012;213:107–115. 9. Ursini CL, Cavallo D, Colombi A, et al. Evaluation of early DNA damage in healthcare workers handling antineoplastic drugs. Int Arch Occup Environ Health. 2006;80:134– 140. 10. Gilles L, Favier B, Catillon F, et al. Improvement of quality of practices for the preparation of cytotoxic drugs: results
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of a “before-after” study [in French]. Bull Cancer. 2009;96:839–849. El-Ebiary AA, Abuelfadl AA, Sarhan NI. Evaluation of genotoxicity induced by exposure to antineoplastic drugs in lymphocytes of oncology nurses and pharmacists. J Appl Toxicol. 2013;33:196–201. Mader RM, Kokalj A, Kratochvil E, et al. Longitudinal biomonitoring of nurses handling antineoplastic drugs. J Clin Nurs. 2009;18:263–269. Deng H, Zhang M, He J, et al. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis. 2005;20:351–357. Kopjar N, Garaj-Vrhovac V. Application of the alkaline comet assay in human biomonitoring for genotoxicity: a study on Croatian medical personnel handling antineoplastic drugs. Mutagenesis. 2001;16:71–78. Laffon B, Teixeira JP, Silva S, et al. Genotoxic effects in a population of nurses handling antineoplastic drugs, and relationship with genetic polymorphisms in DNA repair enzymes. Am J Ind Med. 2005;48:128–136. Cavallo D, Ursini CL, Perniconi B, et al. Evaluation of genotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees. Mutat Res. 2005;587:45–51. Ratner PA, Spinelli JJ, Beking K, et al. Cancer incidence and adverse pregnancy outcome in registered nurses potentially exposed to antineoplastic drugs. BMC Nurs. 2010;9:15. Quansah R, Jaakkola JJ. Occupational exposures and adverse pregnancy outcomes among nurses: a systematic review and meta-analysis. J Womens Health (Larchmt). 2010;19:1851–1862. Lawson CC, Rocheleau CM, Whelan EA, et al. Occupational exposures among nurses and risk of spontaneous abortion. Am J Obstet Gynecol. 2012;206(327):e1–e8. Biro A, Fodor Z, Major J, Tompa A. Immunotoxicity monitoring of hospital staff occupationally exposed to cytostatic drugs. Pathol Oncol Res. 2011;17:301–308. Gilles L, Favier B, Lombard I, et al. Cytotoxic drugs: evaluation of the impact of purging infusion lines on exposure of nursing staff [in French]. Arch Mal Prof. 2004;65:9–17. Merger D, Tanguay C, Langlois E, et al. Multicenter study of environmental contamination with antineoplastic drugs in 33 Canadian hospitals. Int Arch Occup Environ Health. 2013 Mar 8. [Epub ahead of print]. Diem E, Ivancsits S, Rudiger HW. Basal levels of DNA strand breaks in human leukocytes determined by comet assay. J Toxicol Environ Health A. 2002;65:641–648. Wallemacq PE, Capron A, Vanbinst R, et al. Permeability of 13 different gloves to 13 cytotoxic agents under
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Address correspondence to: Catherine Rioufol, PharmD, PhD, 165 chemin du grand Revoyet, 69495 Pierre Benite Cedex, France. E-mail: [email protected]
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Administration of Anticancer Drugs: Exposure in Hospital Nurses Catherine Rioufol, PharmD, PhD1,2; Florence Ranchon, PharmD, PhD1,2; Ve´rane Schwiertz, PharmD2; Nicolas Vantard, PharmD2; Elsa Joue, PharmD2; Chloe´ Gourc, PharmD2; Noe´mie Gauthier, PharmD2; Marie Gabrielle Guedat, PharmD2; Gilles Salles, MD, PhD3; Pierre-Jean Souquet, MD4; Bertrand Favier, PharmD, PhD5; Laurence Gilles, PharmD5; Gilles Freyer, MD, PhD1,6; Benoıˆt You, MD, PhD1,6; ˆme Guitton, PharmD, PhD7 Ve´ronique Trillet-Lenoir, MD, PhD1,6; and Je´ro 1
University Claude Bernard Lyon, Lyon, France; 2Hospices Civils de Lyon, Groupement Hospitalier Sud, Clinical Oncology Pharmacy Department, Lyon, France; 3Hospices Civils de Lyon, Groupement Hospitalier Sud, Department of Haematology-University Claude Bernard, Lyon, France; 4Hospices Civils de Lyon, Groupement Hospitalier Sud, Department of Pneumology, Lyon, France; 5Centre Le´on Be´rard, Pharmacy Department, Lyon, France; 6Hospices Civils de Lyon, Groupement Hospitalier Sud, Department of Oncology, Lyon, France; and 7 Hospices Civils de Lyon, Groupement Hospitalier Sud, Chemotherapy Targeting in Oncology LaboratoryUniversity Claude Bernard Lyon, Faculty of Pharmacy, Toxicology Laboratory, Lyon, France ABSTRACT Background: Even though anticancer drugs are prepared in dedicated pharmaceutical units, nurses remain exposed to cytotoxic agents during administration to patients. Objective: The aim of this study was to assess this occupational exposure during the intravenous line– purging procedure at the patient’s bedside before administration in oncology departments. Methods: This prospective study was conducted over a 4-week period in the hematology and oncology departments at a university hospital. Amounts of doxorubicin and cyclophosphamide on the surface of nurses’ gloves were measured after the intravenous line purge of the infusion bag and the connection to the patient. For this purpose, gloves were washed with sterile water, following a validated procedure. Quantification of the 2 drugs into the water was performed using LC-MS/MS. Results: After 59 chemotherapy administrations, 30.5% of gloves were contaminated. Despite extremely low volumes of contamination (0.08–6.28 mL), amounts collected ranged from 190 to 2500 ng per pair of gloves that tested positive for doxorubicin (median, 1600 ng) and from 130 to 32,600 ng with cyclophosphamide (median, 2700 ng). Conclusions: The intravenous line purge preceding antineoplastic infusion bag administration is a potential source of contamination in nurses. Contaminations
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appear to be invisible but frequent (in 430% of cases). Therefore, intravenous line purging performed under appropriately safe conditions should be mandated in pharmaceutical units dedicated to injectable-drug preparation. This measure should be included as a standard hospital practice as a matter of urgency. (Clin Ther. 2014;36:401–407) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: antineoplastic, intravenous line purge, nurses, occupational exposure.
INTRODUCTION Aside from their curative effects, the widespread use of antineoplastic agents in the treatment of cancer has led to an increased concern of handling these drugs by the pharmacy team, nurses, and physicians because of their potential carcinogenic, mutagenic, and/or teratogenic effects in humans.1 During the past 20 years, safety standards have been issued to protect health care workers.2,3 In chemotherapy preparation, one of the first measures of preventing exposure in health care workers is to Accepted for publication January 26, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.01.016 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
401
Clinical Therapeutics centralize the preparation of cytotoxic drugs in pharmaceutical-preparation units, using specific guidelines, appropriate organizational measures, and specialized technical equipment, such as vertical laminar airflow safety hoods, or isolators, and protective clothing, including double pairs of gloves. For the administration step, gloves must be worn by nurses at all times when hazardous drugs are being handled. Although these guidelines are advanced to reduce workers’ exposure, recent studies have shown that recommendations were not always applied4–6 and that workplace contamination4,5,7–10 and occupational exposure have decreased but are still present. Worker exposures have been assessed by studies of biological markers. Cytogenetic effects, such as mutagenic activity in urine, micronucleus induction, chromosomal aberrations, and sister-chromatid exchanges, were reported.6,11–13 More recently, early DNA damage revealed with single-cell gel electrophoresis (CometAssay, Trevigen Inc, Gaithersburg, Maryland) were shown in health care workers handling antineoplastic drugs.4,6,9,13–16 Moreover, potential various acute (short-term) and chronic (long-term, eg, cancer) effects of residual exposure to hazardous drugs have been described in several epidemiologic studies.17–20 Although both the pharmacy team and nurses were regularly handling antineoplastic drugs, studies showed lower frequencies of genetic damage in pharmacists versus nurses,4,11,16 which could be explained by greater protective measures applied by pharmacists versus nurses, for whom gloves were the only protective measure employed.11 The procedure of purging the line with antineoplastic solution by nurses just before infusion-bag administration to patients was identified as a potential source of contamination, as has been the aerosolization or spilling of anticancer drugs. This route of contamination has been quantified in only 1 study.10 The procedure of purging the line with saline solution during chemotherapy preparation in the centralized pharmacy unit could be a solution to avoiding nurses’ exposure. However, for economic reasons (because of the necessary purchase of supplementary intermediate medical devices), this procedure is not applied in some hospitals. The aim of the present study was to assess occupational exposure in nurses during the intravenous line–purging procedure at the patient’s bedside before administration of antineoplastic infusion prepared by the pharmacy. According to the results, this study could be a major argument for hospital decision makers to change practices.
402
MATERIALS AND METHODS Study Design This prospective study was conducted in a 1200bed teaching hospital specializing in cancer patients’ care in France. Antineoplastic-infusion bags were prepared in the centralized pharmaceutical preparation unit under laminar vertical air-flow safety hoods. During the chemotherapy-preparation step, pharmacy technicians wore protective clothing, nursing caps, safety glasses, masks, and a double pair of gloves. The pharmaceutical-preparation procedures do not include the purging-line step, which is realized at the time of the administration by the nurse. At the end of the preparation step, the chemotherapy-infusion bag is packed in a sterile field under the hood and placed in a disinfected plastic bag outside the hood by the pharmacy technician, limiting chemotherapeutic contamination on the plastic bag. Then the preparation is transported from pharmacy to the day care unit in a box intended for hazardous drugs.
Nurse Recruitment Fifteen voluntary nurses (only women) from a hematology and oncology day care unit were involved in the study. These nurses are usually involved in antineoplastic-drug administration; 100% had 42 years of experience. The day hospital performs up to 30 drug administrations per day. Before administration, the nurse inserts the spike of the line into the tubing port of the infusion bag containing the antineoplastic preparation. The intravenous line (Eurofix, Braun Laboratories, Pasadena, California) is then purged with the cytotoxic solution at the patient’s bedside. An integrated end-line hydrophobic filter stopped the solution before expulsion from the set. Nurses were informed about the aim and the procedures of the study. Informed consent was signed by all participating subjects.
Glove Contamination and Sampling Two common cytotoxic drugs, doxorubicin and cyclophosphamide, were identified and quantified on the surfaces of the nurses’ gloves after administration to the patient. A total of 60 infusion bags were selected for the 4-week period of the study. For each selected infusion bag, 1 pair of nonsterile gloves was worn by the nurse before the line was purged and connected to the patient. At the end of the procedure, potential traces of antineoplastic drug on the surface
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C. Rioufol et al.
Figure. Immersion of the nurse’s gloved hands in 100 mL of sterile water for injection (after connecting the infusion bag).
of the gloves were collected using an adapted procedure developed by Gilles et al.10,21 After connecting the infusion bag to the patient, nurses immersed their 2 gloved hands into a single-use, open plastic box (28 21 5 cm) containing 100 mL of sterile water for injection and carried out a 1-minute standardized friction of the 2 gloved hands. Six steps of 10 seconds each were implemented (Figure): friction of the (1) fingers; (2) palms; (3) back of the hands; and between the fingers of the (4) right and (5) left hands; and (6) circular friction of both hands in the solution. Then sterile water for injection was collected in 100-mL glass vials, shaken, and aliquoted in 3-mL glass tubes. Samples were stored at –201C until assay.
Doxorubicin and Cyclophosphamide Quantification Quantification of doxorubicin and cyclophosphamide was performed by LC-MS/MS (Quantum-Ultra, Thermo Fisher Scientific Inc, Rochester, New York). The standards of doxorubicin, daunorubicin, ifosfamide, and cyclophosphamide were supplied from Sigma (St. Quentin Falavier, France). Stock solutions of the 4 compounds were prepared in methanol at a concentration of 1 mg/mL and stored at 41C. These solutions were then diluted with water to yield a series of spiking standard solutions. Doxorubicin and cyclophosphamide were added to water to yield final concentrations from 1 to 1000 ng/mL, corresponding to the calibration curves. Daunorubicin and ifosfamide were used as internal standards for doxorubicin and
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cyclophosphamide, respectively. An internal standard is a compound structurally close to the analyte. A known quantity of standard is added to the unknown before any manipulations; thus, the ratio of standard to analyte remains constant and allows for obtaining more accurate results. For cyclophosphamide, chromatographic separation was performed on a Hypersil Gold 3-mm (150 2.1-mm) analytical column (Thermo Fisher). The mobile phase was a solution of water/formic acid at 0.1% (vol/vol) (phase A) and acetonitrile/formic acid at 0.1% (vol/vol) (phase B). For doxorubicin, chromatographic separation was performed on an Atlantis Hilic 3-mm (150 2.1-mm) analytical column (Waters Corporation, Milford, Massachusetts). The mobile phase consisted of an acetate ammonium buffer at pH 5 (phase A) and acetonitrile (phase B). In both cases, the mobile phase was delivered through the column (temperature maintained at 301C) at a flow rate of 200 mL/min. The mass spectrometer was operated in positive ion mode with electrospray source. For the quantification of doxorubicin and cyclophosphamide, the transitions m/z 544.2 361.0 (doxorubicin) and m/z 261.0 - 140.0 (cyclophosphamide) were monitored using the selected reaction monitoring. Peak area ratios of doxorubicin and cyclophosphamide to the respective internal standard measured at each nominal concentration were used to construct weighted (1/concentration) least-squares linear regression curves. The samples, previously frozen, were brought to room temperature and well-vortexed, and an appropriate volume of a solution of internal standard was added and 10 mL of the mixture was injected into the LC-MS/MS apparatus. The lower limits of quantification of doxorubicin and cyclophosphamide were each 1 ng/mL.
Calculation of the Amount of Drugs Present on the Surfaces of Gloves The concentration of each drug present in the samples was measured from calibration curves (from 1 to 1000 ng/mL). The quantities of both compounds on the surfaces of pairs of gloves were determined by multiplying the concentration measured by 100 (corresponding to the volume of water used for washing the gloves). The concentration of the compound present in the infusion administered to the patient and the quantity measured on the gloves were known, and the volume of infusion leading to the contamination was calculated.
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Table. Correspondence between concentration of anticancer drug in infusion bag, amount of drug and volume of cytotoxic solution collected per pair of contaminated gloves. Doxorubicin CIB (mg/mL)
Cyclophosphamide
QMG (mg)
Volume of contamination (mL)
0.50 2.3 1.6 73 2.5 0.19
380 1000 410 860 1000 350
Mean (1) (SD)
CIB (mg/mL)
QMG (mg)
Volume of contamination (mL)
1.32 2.30 3.90 84.88 (*) 2.50 0.54
4500 3960 5190 4500 5130 5190 4290 6000 5700 3000 2920 6000 1690
2.5 22.9 32.6 1.7 1.2 0.8 2.7 3.0 1.0 4.0 7.1 11.9 0.13
0.55 5.78 6.28 0.38 0.23 0.15 0.63 0.5 0.17 1.33 2.43 1.98 0.08
2.11 (1.27)
Mean (SD)
1.58 (⫾2.11)
CIB ¼ Concentration inside the infusion bag administered to the patient (mg/mL); QMG ¼ Quantity measured on gloves (mg); Volume of contamination (mL) ¼ (QMG/CIB) x 1000. * the mean excludes the outlying value marked
Statistical Analysis Descriptive analyses were realized by χ2 test, and P o 0.05 was considered as statistically significant.
RESULTS Overall, 60 samples were analyzed from 33 administrations of doxorubicin (100-mL infusion bags) and 27 administrations of cyclophosphamide (250-mL infusion bags). A total of 19 samples were positive; 1 result was considered as an outlier and was not included in the analysis. Gloves appeared to have been contaminated during the purge before the administration of the anticancer drugs in 30.5% of cases (18/59). Except for the outlier, 18 samples (30.5%) were positive, that is, 5 samples of doxorubicin (16% of doxorubicin preparations) and 13 samples of cyclophosphamide (48% of cyclophosphamide preparations). The frequency of contamination was greater with the 250-mL infusion bags of cyclophosphamide versus
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the 100-mL infusion bags of doxorubicin (P ¼ 0.007 [χ2 test]). The drug amounts collected on positive gloves ranged from 0.19 to 2.5 mg per glove pair with doxorubicin (median, 1.6 mg) and from 0.13 to 32.6 mg with cyclophosphamide (median, 2.7 mg). From the whole data, the average volume of contamination was calculated as 1.73 mL per pair of positive gloves. Complete data are shown in the Table.
DISCUSSION Although safety standards for cytotoxic drug handling have considerably been improved over the past 2 decades, workplace contamination and occupational exposure are still reported, which is a particularly worrying issue for all hospital staff specializing in oncology.22 Indeed, workplace contamination was still recently reported in oncology wards including both day-care
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C. Rioufol et al. and inpatient units.9,16 Correlation between the amount of drugs handled and the extent of surface contamination remains controversial, highlighting the necessity of systematic safety procedures.5,8,10 This concern has been urged by recent studies in which novel abnormalities, such as early DNA damage, were detected in health care workers handling antineoplastic drugs.9,12,23 Moreover, the use of personal protective equipment (ie, gloves and masks) decreased, but did not prevent, primary DNA damage.4,12 These findings were expected given the well-known permeability of gloves to cytotoxic agents.24 Even though anticancer drugs were prepared by the pharmaceutical team, contamination was detected in oncology wards, particularly in administration areas.9,11,16 Nurses seem to be less at risk for aerosol inhalation than through other means of exposure, such as direct skin contact with contaminated intravenous tubing, or patients’ excreta with hand-to-mouth contact.25 Gilles et al21 first investigated the intravenousline purge preceding infusion-bag administration and confirmed that this step was a potential source of contamination in nurses. The formation of aerosolized cytotoxic solution was demonstrated, confirming potential exposure. In agreement with Gilles et al, the present study demonstrated that contact between droplets of cytotoxic solution and gloves occurred during the purge procedure, leading to exposure in nurses. The high observed rate of glove contamination (430%) highlights strikingly substantial exposure occurring during the intravenous-line purge, even though the infusion bags had been prepared in the centralized pharmaceutical-preparation department. Because no "safe" occupational-exposure limit exists, the amount of antineoplastic contamination should be kept as low as possible. The present study reported a high rate of glove contamination, but with a low volume (ranging from 0.08–6.28 mL of cytotoxic solution, except for 1 outlier), and positive amounts of cytotoxic drugs (medians, 1600 ng [doxorubicin] and 2700 ng [cyclophosphamide]). The corresponding average amounts were in line with those collected in a previous study detecting 5fluorouracil (10,800 ng).21 Larger infusion-bag volumes of cyclophosphamide (250 mL) were correlated with more frequent contamination, likely suggesting the difficulty in handling large bags of cytotoxic preparations. Correlation with other, larger infusionbag volumes (eg, 500 or 1000 mL) remains to be
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confirmed using the same antineoplastic to avoid confounding factors. Such results not only confirm the necessity of wearing protective gloves during administration but also further demonstrate that the pharmaceuticalpreparation process should be extended to intravenous-line purging, as strongly suggested by Fransman et al.7 Many purge systems are available and have to be tested and adjusted to hospitals’ standard practices. These efforts are all the more justified as new drugs with unknown long-term effects are developed. These drugs involve chemicals with different structures, origins, and activities, constituting a vast heterogeneous class of compounds such as immunotherapy (ie, monoclonal antibodies) and cell and gene therapy (ie, vaccine). In the face of such uncertainties, vigilance needs heightening to protect staff against repetition of past bad experiences.
Study Limitations The present study focused only on the contamination of the gloves, without assessment of potential clinical effects in nurses. The limitations of this study include the small sample size (limited to 60 preparations) in only 1 hospital. Work practices, techniques, and experience in nurses may influence these results and have to be investigated. The use of a limited number of marker compounds to evaluate exposure could be limitative.
CONCLUSIONS Despite several guidelines and safety recommendations for anticancer-drug handling, including the use of protective equipment and the preparation of injectable anticancer drugs by a dedicated pharmaceutical unit, significant trace amounts of these agents were found on nurses’ gloves, with potential genotoxic risk. The intravenous-line purge preceding antineoplastic infusion–bag administration is a potential source of exposure in nurses. Invisible and frequent (in 430% of cases) contamination with significant amounts of cytotoxic drugs may lead to potential serious consequences. Adapted strategies to prevent such exposure should be developed to reduce the risk for contamination among exposed workers. The mandatory intravenous line purge under appropriately safe conditions in pharmaceutical units dedicated to injectable-drug preparation should be considered as
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ACKNOWLEDGMENTS The authors acknowledge the medical, pharmaceutical, and nursing teams at the Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
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CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.
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Address correspondence to: Catherine Rioufol, PharmD, PhD, 165 chemin du grand Revoyet, 69495 Pierre Benite Cedex, France. E-mail: [email protected]
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